Seminars in Cancer Biology 88 (2023) 123–137

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Seminars in Cancer Biology

journal homepage: www.elsevier.com/locate/semcancer

Transcriptional factors targeting in cancer stem cells for tumor modulation

Archana Chaudhary a, Syed Shadab Raza b, Rizwanul Haque a, *
a
Department of Biotechnology, School of Earth Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
b
Laboratory for Stem Cell & Restorative Neurology, Era’s Lucknow Medical College and Hospital, Era University, Lucknow, India

A R T I C L E I N F O A B S T R A C T

Keywords: Cancer Stem Cells (CSCs) are now considered the primary "seeds" for the onset, development, metastasis, and
Cancer Stem Cells (CSC) recurrence of tumors. Despite therapeutic breakthroughs, cancer remains the leading cause of death worldwide.
Transcription factors (TFs) This is because the tumor microenvironment contains a key population of cells known as CSCs, which promote
Octamer-binding transcription factor 4 (OCT-4)
tumor aggression. CSCs are self-renewing cells that aid tumor recurrence by promoting tumor growth and
Sex determining region Y-box 2 (SOX-2)
persisting in patients after many traditional cancer treatments. According to reports, numerous transcription
factors (TF) play a key role in maintaining CSC pluripotency and its self-renewal property. The understanding of
the functions, structures, and interactional dynamics of these transcription factors with DNA has modified the
hypothesis, paving the way for novel transcription factor-targeted therapies. These TFs, which are crucial and are
required by cancer cells, play a vital function in the etiology of human cancer. Such CSC TFs will help with gene
expression profiling, which provides crucial data for predicting the prognosis of patients. To overcome anti-
cancer medication resistance and completely eradicate cancer, a potent therapy combining TFs-based CSC tar­
gets with traditional chemotherapy may be developed. In order to develop therapies that could eliminate CSCs,
we here concentrated on the effect of TFs and other components of signalling pathways on cancer stemness.

1. Introduction
It was first proposed in 1994 that tiny groups of cancer cells called
Cancer Stem Cells (CSCs) are responsible for the formation of the bulk of
tumor cells. These studies showed that while the bulk of malignant cells
fail to engraft and cause disease, a tiny percentage of human leukemia
cells could cause leukemia in SCID (severe combined immunodeficient)
mice [1,2]. Further research on hematological malignancies led to the
hypothesis that CSCs, like normal stem cells, live at the apex of a hier­
archical cluster of mature cells, are capable of self-renewal, and can
produce numerous progeny that are considered "mature." Critical in­
vestigations carried out, afterwards discovered CSC activity in a range of
malignancies [3]. As we all know, metastasis and reoccurrence
following successful primary tumor elimination are two important ob­
stacles to cancer therapy [1,4]. As a result, cancer eradication necessi­
tates the elimination of CSCs, which persist after treatments cause tumor
relapse or recurrence [5,6]. Since CSC can produce any sort of cell
observed in the majority of the tumor, they can start the development of
secondary tumors [7,8]. CSCs are cell lineages that exist within a
growing tumor in various malignancies, such as intestinal adenomas,
glioblastomas, and squamous skin tumors. These tumors have given
direct and convincing experimental evidence to support the idea that
some tumor cells have a small number of fast-growing and self-renewing
cell populations [8,10], as well as the implications of this finding for
therapy (Fig. 1). The role of TFs in tumor onset and growth has recently
received a lot of attention, especially since the discovery of multiple
stemness factors in human somatic cells that can cause cell reprogram­
ming to resemble embryonic stem cells [11,12].
2. Role of TFs in CSCs
Transcription factors are key gene expression regulators that are
necessary for CSC self-renewal and pluripotency [8]. One critical goal is
to find master transcription factors that determine the identity of CSCs.
Years of cell transplantation research demonstrated that abnormal
expression of transcription factors like OCT-4, NANOG, and SOX-2 iso­
forms and pseudogenes has a significant impact on cancer trans­
formation, metastasis, and carcinogenesis, though the precise
underlying mechanisms remain unknown [10,13]. Novel approaches
that specifically target CSCs while causing no harm to normal cells are
desperately needed to advance current cancer treatment regimens.
There is a wealth of evidence that OCT-4, SOX-2, and NANOG over

* Corresponding author.
E-mail address: rhaque@cub.ac.in (R. Haque).

https://doi.org/10.1016/j.semcancer.2022.12.010
Received 13 July 2022; Received in revised form 29 December 2022; Accepted 30 December 2022
Available online 2 January 2023
1044-579X/© 2022 Published by Elsevier Ltd.
A. Chaudhary et al.
expression occurs in human malignancies, and is linked with tumor
development, metastasis, and distant recurrence after
chemo-radiotherapy [10,13–15]. Over expression of OCT-4, SOX-2 and
NANOG in tumor stem cells modifies signaling pathways to prevent
apoptosis [10,16–18]. The amounts of OCT-4, NANOG, and SOX-2
mRNA transcripts along with markers of stem cells found in cancer
cells and in niches of CSC are usually greater than those found in
non-tumor tissue [8,15,16]. A number of human malignancies,
including breast cancer, prostate cancer, and oral squamous carcinoma
cells, have been shown to co-upregulate the expression of OCT-4,
NANOG, and SOX2 [19]. It has been shown that OCT-4, the most sig­
nificant pluripotent factor, is up-regulated in a number of tumor cells,
including human oral squamous cell carcinoma, murine Lewis lung
carcinoma, bladder cancer, and seminoma cancer [10,19]. Transcrip­
tional factors linked to stemness can be specifically targeted to treat
different types of tumor illnesses. These stem cell factors promote the
self-renewal properties of CSCs through interactions with various tran­
scription factors, including Stat3, Zic3, and Hesx1, which can exhibit
abnormal expression in a variety of human malignancies [20]. However,
very little research has been done on the regulating mechanism of
transcription factors and their role in mediating CSCs’ stemness. Recent
studies showed that CSC transcription factors could keep CSCs stem-like
by encouraging the expression of genes relevant to stemness[10,20]. The
key player in the reprogramming of breast CSCs is the glycolysis gate­
keeper PDK1, which also offers a potential treatment for breast cancer
[21]. Additionally, it has been shown that NFIs (the nuclear factor one),
a transcription factor that is crucial for the growth of numerous
mammalian organ systems, regulate the accessibility of chromatin at
distal regulatory regions that facilitate the metastasis and growth of
CSCs, as well as its remodeling and epigenetic regulation of gene
expression[22]. Apart from this, STAT3 also has a key role in controlling
both healthy stem cells and tumor stem cells, which are physically and
functionally linked with p63, a member of the p53 protein family [23].
3. Regulation of TFs in various cancer stem cells’ stemness
Most of the TFs are highly up-regulated in certain cancers such as
glioblastomas, colonic adenomas, and squamous skin tumors [10,24,
Fig. 1. The theory of CSC resistance and its therapeutic implications are illustrated by contrasting CSC targeted therapies with conventional cancer therapies. CSCs
can survive the cell death caused by conventional chemotherapy because of their distinct drug-resistance characteristics and plasticity, allowing them to grow new
tumors. It is proposed that CSC targets and bulk tumor ablation be used in combination therapy to enhance cancer patients’ clinical outcomes.
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25], but consistent changes in their gene expression, level of proteins,
and post-translational modification states have not been observed in the
majority of malignancies [26]. Evidence recently suggested that Zeb1 (a
zinc finger E-box), an essential transcriptional regulator in hematopoi­
esis that controls HSC renewal, multilineage differentiation fates, and
apoptosis, must be carefully coordinated in order to reduce leukemic
potential in AML[27]. In addition to the therapeutic approach of CSC
TFs, the limited cross reactivity of CSC surface markers with normal
tissue cells makes them potential therapeutic targets for CSCs [29]. The
most frequently utilized markers for CSC research and cancer thera­
peutic targets are nestin, CD133, and CD44. Colon CSCs, which are
identified by the cell surface markers CD133, CD24, and CD44, are
among the CSCs that have been shown to have a role in the growth of
tumors, treatment resistance, and the spread of the disease to other or­
gans. Reports suggested that high levels of nestin, CD44/CD133, and
OCT-4 expression were present in pancreatic CSCs, which made them
more resistant to gemcitabine than normal pancreatic cells. They are
also strong anti-apoptotic but have limited proliferative abilities [29,
30]. Therefore, the distinct population of pancreatic stem cells may be
crucial in the emergence of widespread metastases and multidrug
resistance in pancreatic cancer. Researchers also showed that autophagy
and the maintenance of tumor cells with upregulated CD44 and down­
regulated CD24, which are common features of breast CSCs, have a
mechanistic link. Autophagy inhibition increased CD24 gene transcrip­
tional activation, enhancing the phenotype of CD44 (+)CD24(+) cells
that resembles epithelial cells rather than the mesenchymal CD24
(-/low) CD44(+) offspring. Treatment with chloroquine increased the
proportion of CD24 (+) cells while concurrently decreasing the consti­
tutive upregulation of vimentin in breast cancer cell lines [31]. A range
of malignancies, including lung, pancreatic, and prostate cancers, have
been discovered to have significant nestin expression [30,32]. It has
been shown that transformed cells from a range of human tumors ex­
press nestin along with other CSC TFs, and it has been proven that this
expression is associated with the clinical development of particular tu­
mors [30]. Increased nestin expression indicates that converted cells are
young and invasive and is related to tumor grade in a variety of tumor
forms [30]. Additionally, a correlation between nestin expression levels
and the clinical course of the disease was discovered for melanoma,
A. Chaudhary et al.
ovarian carcinoma, breast cancer, gastrointestinal malignancies,
gastrointestinal malignancies, germ cell tumors, and osteosarcoma
[33–39]. In these cancers, nestin expression is therefore thought to be a
predictive marker; nevertheless, its prognostic usefulness needs to be
confirmed in large cohorts of patients. The common stem cell TFs OCT-4,
NANOG, CD133, SOX-2, and nestin are expressed by CSCs in prostate
cancer patients [40]. Furthermore, CSCs were isolated from human­
pancreatic cancer using sphere creation, and nestin, CD44, CD133,
NANOG, and OCT-4 expression in these cells was discovered [30,41]. It
is interesting to note that breast CSCs also express nestin and OCT-4,
exhibit higher tumorigenicity by developing mammospheres in an
invitro environment [42]. Compared to cells with limited nestin
expression, those with high nestin expression had a 100-fold higher
tumorigenicity [42,43]. However, nestin was knocked down in breast
CSCs, resulting in cell cycle arrest, induced apoptosis, and suppression of
spontaneous EMT and cell migration [43]. Nestin’s molecular silencing
interfered with the induction of catenin/Wnt, a crucial route for
signaling in breast CSCs [43]. In addition to this, younger age, higher
grades of malignant tumors, lymph node metastases, and poorer sur­
vivals have all been linked to nestin/OCT-4 positivity in cancer tissues
[42,43]. Nestin and other CSC markers have been shown to co-express
with other known CSCs TFs, such as SOX-2, NANOG, OCT-3/4, KLF4
and MYC in circulating breast cancer cells [44]. Using an in silico
translational approach, researchers hypothesized that the amalgamation
of these CSC markers has predictive value in a significant cohort of
colorectal cancer patients [28]. Life-threatening malignancies may be
completely cured by such treatments that target TFs along with CSC
markers, which have significant potential for eliminating the CSC pop­
ulation. So here, we will look at the role of various TFs in the growth of
CSCs as well as the potential of TF networks as direct and indirect
therapeutic targets in CSCs.
4. Different types of transcription factors in CSCs
Researchers demonstrated that cancer is caused by a tumor cell
subpopulation with stem cell characteristics, which were later dubbed
CSCs [45]. Despite advancements in terms of diagnosis and therapy, the
tumor disease prognosis remains deplorable, and the patients’ long-term
cure rate has plateaued within the last 30 years [46]. CSCs are respon­
sible for treatment failure, and it has been established that aggressive
cancer cells exhibit high expressional levels of various transcription
factors such as OCT-4, SOX, NANOG, and KLF-4, among many others
that have been designated as distinct markers [10,46]. Despite intensive
attempts to discover CSCs, novel therapeutic strategies for CSC eradi­
cation remain elusive due to our limited understanding of transcrip­
tional regulation in CSC biology. It will be crucial to comprehend how
the TFs interact to promote normal cellular growth rather than malig­
nant outcomes in order to produce more efficient selective ligands that
can combat CSCs in the future with fewer adverse effects. Additional
investigation into the features of such transcription factors and the CSC
regulation mechanism could aid in the identification of a potential
molecular target for therapeutic intervention in a variety of malig­
nancies. We illustrate how OCT-4, NANOG, and SOX-2 are regulated in
various tumors and how they are usually up-regulated to either inhibit
or activate the cancer-related process.
5. Octamer-binding transcription factor 4 (Oct4)
The wealth of data demonstrating the role of CSCs in the context of
chemo resistance has fueled interest in OCT-4. The homeo domain
transcription factor Octamer-binding transcription factor 4 (OCT-4) has
long been recognized as a master controller of pluripotency and self-
renewal properties [47]. According to a large body of research, OCT-4
has also been found in tumor cells and tissues, as well as in a discrete
subset of undefined tumor-initiating cells (TICs), which are important
for tumor development, metastasis, and treatment-resistant cancer[10,
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47]. OCT-4, also known as Pou5f1, is a transcription factor that regulates
the pluripotency of ESCs (embryonic stem cells) [25]. It induces cell
proliferation by regulating T-cell leukemia/lymphoma1 (TCL1) tran­
scription and upregulating AKT1 kinase activity [48]. The
OCT-4/Akt1/Tcl1 pathway is activated when OCT-4 is activated, and
tumor cells undergo apoptosis inhibition [47]. Different tumors activate
or suppress different cancer-related pathways, but it appears that OCT4,
NANOG, and SOX-2 are always up-regulated to either activate or sup­
press OCT-4/Tcl1/Akt1 pathways [47,48]. OCT-4 overexpression pro­
motes carcinogenesis and suppresses cancer cell death in cervical cancer
cells [24]. According to a chromatin immunoprecipitation study, OCT-4
increases miR-125b production by binding directly to the miR-125b-1
promoter [49–52]. When the miR-125b response element was changed
or eliminated, the untranslated region reporter activity of wild-type
BAK1 3′ was significantly suppressed in the Luciferase assay [47,52].
OCT-4 post-translational modification alters its activity and calls for
further research into its relationship to chemo resistance and prognosis.
Radiation- or chemotherapy enriched CSCs in various malignancies
showed phenotypic changes as well as an increase in stem cell marker
expression such as OCT-4, SOX-2, NANOG, CD133, and ALDH, although
the mechanisms of OCT-4 in promoting chemo resistance are not well
understood [47]. In a number of CSCs, OCT-4 is implicated in tumor
vasculogenesis. In the year 2020, Liu et al. demonstrated that liver
cancer stem cells (LCSCs) can undergo trans-differentiation into endo­
thelial cells in response to endothelial induction, that
endothelium-specific functions and markers exist in vitro, and that
LCSCs contribute to neo vasculogenesis in vivo [52]. Transcription
factors like OCT-4, SOX-2, and NANOG show tremendous clinical
promise. They can be effective carcinogenesis markers and molecular
switches that regulate the fate of CSC cells during the cancer develop­
ment [53,54]. CSCs exhibit a lot of OCT-4 during the occurrence and
growth of malignant tumors and its degree of expression is positively
connected with various malignancies.OCT-4 was found in both the
cytoplasm and nucleus of breast cancer cells, according to the findings
[54,55]. The human OCT-4 gene can produce at least 3 transcripts,
referred to as pseudogenes (OCT-4A, OCT-4B, and OCT-4B1), and 4
protein isoforms through alternative splicing and alternative translation
initiation (OCT-4A, OCT-4B-190, OCT-4B-265, and OCT-4B-164) [53,
56]. OCT-4 has a slightly larger molecular weight in bladder tumor cells
than in normal bladder cells, which may be the result of distinct post­
translational modifications of OCT-4 [57]. OCT-4, SOX-2, and NANOG
are deregulated in signaling pathways, although their distinct behaviors
in ESCs and CSCs may be influenced by the expression of their isoforms
and pseudogenes. Breast cancer specimens were found to express two or
more factors that induce stem cells, like c-MYC, KLF4, OCT-4, NANOG,
and SOX-2[36,37,57,58]. Therefore, CSC-inducing factors in CSCs could
be one of the crucial areas for cancer research in the future. OCT-4 was
found to be highly activated in CD24/CD44 (+) tumor cells, suggesting
that it could be a biomarker for cancer metastasis, progression, and
progression [58]. Breast cancer stem-like cells may express more CD44,
CXC chemokine receptor-4 (CXCR4), and OPN (osteopontin) while
expressing less CD24 [58]. In patients with surgically removed rectal
cancer (RC) getting adjuvant therapy, the expression of OCT-4, NANOG,
and SOX-2 was investigated for their associations with
clinico-pathological traits and overall survival. It was discovered that
OCT-4 expression in tumor tissue can serve as a standalone prognostic
marker and is related to poor differentiation, tumor size, and its stage
[59]. The Raf-kinase antagonist protein, which inhibits metastasis and
serves as a chemo-immuno-sensitizer to medication- or
immune-mediated apoptosis, is inversely linked with the expression of
OCT-4,suppress SOX-2 expression by inhibiting the route for
mitogen-activated protein kinase and induces NANOG by preventing the
kinase controlled by extracellular signals. Raf-kinase inhibitor proteins
prevent OCT-4 and SOX-2 from forming the heterodimer that is required
to bind to the promoter of NANOG and trigger the transcription of
NANOG. These reports demonstrated a direct link between the
A. Chaudhary et al.
expression of all three TFs and the expression of the Raf-kinase inhibitor
protein, suggesting that this protein’s level of expression may be regu­
lating the phenotype of CSCs [60]. OCT-4 expression, like most stem cell
factors, appears to be important in cancer, with increased as well as
decreased expression interfering with various cancer-related processes.
6. Sex determining region Y-box 2 (SOX-2)
SOX-2 is a crucial transcription factor in CSCs that regulates em­
bryonic stem cell pluripotency as well as other developmental processes
[49]. SOX-2 expression has been linked to breast, colorectal, gastric, and
lung cancers, as well as a link between cancer and stemness[10,61].
SOX-2 functions in CSCs through a number of signaling channels, and
there is evidence that it opposes the Wnt pathway, which promotes
differentiation and may suppress SOX-2 expression [62,63]. In prostate
cancer stem cells (PCSCs), stimulation of Epidermal Growth Factor Re­
ceptor (EGFR) signaling pathways causes a substantial increase in SOX-2
mRNA along with protein levels, promoting CSC self-renewal [47,64].
Further investigation has revealed that the CSC SOX-2 expression status
is at the root of many clinical types of tumors, implying that SOX-2
serves a crucial function in the development of cancer through CSC
amplification [64]. SOX-2 is classified as a proto-oncogene, which
means that amplification, mutation, and overexpression of the SOX-2
gene can result in a variety of malignant diseases with metastasis [10,
61]. SOX-2 amplification is linked to enhanced proliferation, metastasis,
tumor burden, and a poor prognosis [65]. In lung cancer, SOX-2 defi­
ciency reduces CSC tumorigenicity and controls the expression of a
number of cancer-regulating genes, including, c-MYC, NOTCH1, WNT1,
and WNT2 [66]. Furthermore, downregulation of SOX-2 results in cell
cycle arrest, which ultimately leads to a reduced proliferation rate in
glioma, lung and breast cancer cells [61,63]. Another recent study
showed that SOX-2 is expressed in early breast cancers but OCT-3/4 and
NANOG are not, indicating that a variety of variables at the level of
translation and protein synthesis influence gene expression [66]. SOX-2
and DNA (cytosine-5) Methyltransferase 1 (DNMT1) predicted a poor
prognosis for breast cancer. According to reports, the DNMT1/FOXO3a
(Forkhead box protein O3)/Forkhead box protein M1 (FOXM1)/SOX-2
pathway has a significant role in controlling the characteristics of Breast
Cancer Stem Cells(BCSCs), providing prospective therapeutic targets for
breast cancer [67]. SOX-2 overexpression caused mammosphere for­
mation in xenograft tumor models, whereas SOX-2 knockdown inhibited
mammosphere formation and prolonged tumor formation in breast
cancer cell [68]. SOX-2 expression was induced following sphere for­
mation by activation of the distal enhancer of the SOX-2 promoter, the
same element that controls SOX-2 transcription in pluripotent stem cells.
By situating the tumor-initiating event in any cell along the axis of
mammary differentiation, researchers can infer tumor heterogeneity
and highlight SOX-2 reactivation as a key early stage in the development
of breast cancers [68]. Down regulated SOX-2 expression significantly
reduced lung cancer cell metastasis and tumor growth [61,68]. CSCs are
developed and maintained through the SOX-2 signaling pathway, which
is active in CSCs produced from lung cancer cells [66]. It is still unclear
how the SOX-2 signaling pathway and the genes OCT-4 and NANOG
function in the growth and maintenance of CSCs. Previous reports sug­
gest that SOX-2 signaling is involved in the development of CSCs and
that its deregulation can effectively suppress the metastasis and growth
of non-small cell lung carcinoma cells [61]. This TF may control onco­
gene expression in CSCs to aid in the progression of human lung cancer
[66]. SOX-2 binds to specific DNA sequences and acts as transcription
factors to either repress or activate target gene expression using their
highly conserved high mobility group [69,70]. In MCF-7/Rep (rapa­
mycin resistant breast cancer) cells, the exogenous SOX-2 trans gene was
silenced in tandem but the endogenous SOX-2 stemness gene was
distinctly reactivated according to the transcriptional analyses of OCT-4,
SOX-2, KLF-4, and c-MYC transcription factors. Compared to MCF-7
parental cells, some MCF-7/Rep cells, but not all of them, developed
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Seminars in Cancer Biology 88 (2023) 123–137
active alkaline phosphatase (AP) in significant amounts, with signifi­
cantly greater proportions of CD44(+). The genes PRKAA1 (which codes
for the catalytic AMPK 1 (AMP-activated protein kinase1 subunit),
DDIT4/REDD1 (a stress response gene that acts as a negative regulator
of mTOR(Target of Rapamycin), and DEPTOR (a naturally occurring
endogenous inhibitor of mTOR activity) were noticeably down regu­
lated in three separate SOX2-overexpressing CSC-like cell lines.
Insulin-receptor gene expression in MCF-7/Rep cells was differently
upregulated. Immunoblotting tests demonstrated over expression of
p70S6K and enhanced phosphorylation of mTOR in
SOX-2-overexpressing CSC-like cell types, which was consistent with the
downregulation of AMPK expression. Through these reports, researchers
showed that transcriptional suppression of mTOR repressors is an
intrinsic process occurring during the acquisition of CSC-like properties
by differentiated populations of luminal-like breast cancer cells. They
did this by using an in vitro model of the de novo generation of CSC-like
states through the nuclear reprogramming of an established breast
cancer cell line. These reports might open up a new avenue for learning
how to control the AMPK/mTOR pathway to avoid the emergence of
CSCs [71]. Studies have also reported that through the stimulation of the
Rap1/P110 β cascade, aberrant AKT activation supports CSC charac­
teristics in hepatocellular carcinoma (HCC). By increasing SOX-9
expression and improving its protein stability, CD73, a traditional sur­
face marker of multipotent mesenchymal stem cells, contributes signif­
icantly to the maintenance of CSC characteristics. Eradicating CSCs and
reversing Lenvatinib resistance in HCC may be accomplished by tar­
geting CD73 [72]. Studies also suggest that overexpressionof SOX-2may
be closely linked to the malignant transformation of ovarian tumors, as
evidenced by the fact that the level of SOX-2 expression in human
ovarian tumors was directly related to the severity of the cancer [73]. As
a result, SOX-2 promotes tumorigenesis and self-renewal in CSCs while
suppressing differentiation. Therefore, these innovative updates related
to SOX-2 TF might aid in the future creation of effective cancer therapy.
7. NANOG
NANOG is normally silent in normal somatic cells and is only
expressed in germline fibroblasts, ESCs, and in a few cancer cells;
however, altered expression has been observed in lung cancer, breast
cancer, brain cancer, cervical cancer, colon cancer, and gastric cancer
[10,25]. Cell cycle arrest and apoptosis induced by NANOG knockdown
diminish gastric cancer cell growth and metastatic capacity [74].
NANOG was discovered to have anti-tumorigenic properties in glio­
blastoma, prostate, and breast cancer cell lines [10,25,75]. Reports
suggest that NANOG promotes chemo-resistance by increasing
epithelial-mesenchymal transition and cell migration [76,77]. Similarly,
in vivo, NANOG overexpression stimulates tumorigenicity and colony
formation in colorectal CSCs [78,79]. Patients with gastric cancer who
have a high NANOG level are associated with a decreased 5-year sur­
vival rate. NANOG expression is high in primary tumors such as HCC,
and it has been linked to disease progression (stage III/IV of tumor node
metastasis (TNM)) [79,80]. In a study of prostatic cell lines, xenografts,
and primary tumors, NANOG short hairpin RNA was discovered to
inhibit the growth of initial cancer cells in the prostate (PCA) spheres,
tumorigenesis, and clonal growth [76,80,81].
According to a Kaplan-Meier analysis of 43 pancreatic cancer tissue
microarray analyses, a high level of NANOG and OCT-4 expression was
associated with a poor prognosis and a lower chance of survival for the
patient [82]. NANOG is a pro-tumorigenic factor that can be used as a
biomarker in the clinic to diagnose cancer and predict the prognosis and
efficacy of anticancer therapies. Researchers demonstrated that when
human breast CSCs were tested using real-time PCR, they showed higher
expression of NANOG, SOX-2, OCT-3/4,CD34, and Nestin [44]. Based on
the results of qPCR in breast cancer, they revealed that several CSC
transcriptional factors’ expression levels increased in accordance with
the disease’s stage. The gene expression levels, with the exception of
A. Chaudhary et al.
OCT-3/4, were increased in accordance with the stage. Less variation
was seen between stages II-III, although between stages I and II and III
and IV, it was higher [44,68]. Gynecologic tumorigenesis was found to
be significantly impacted by NANOG overexpression [83]. According to
immune histochemical analysis, NANOG andSOX-2 expression were
mentioned as potential candidates for involvement in the initial stages of
breast cancer [68]. Scientists also revealed that NANOG expression was
linked to resistance to hormonal therapy and chemotherapy as well as a
worse prognosis [84]. Breast cancer metastasis and proliferation were
linked to 70 genes, including NANOG, and it was illustrated that the
expression of these genes was connected to prognosis [85]. In light of
this, it appears that NANOG may function as a prognostic indicator both
at the protein and gene levels [86,87]. NANOG removal may also be a
therapeutic goal because it is thought to prevent CSC self-renewal and
identify the source of cancer recurrence and metastasis.
8. Kruppel-like factor 4 (KLF4)
Kruppel-like factor 4 (KLF4), associated with three zinc finger do­
mains on chromosome 9q31, is needed for the generation of cells with
induced pluripotency (iPSCs) [87]. KLF4 expression is lower in
cancerous tissues than in healthy ones, particularly in NSCLC (non-small
cell lung cancer), indicating tumor-suppressing property [88]. KLF4 has
also been discovered to be a tumor suppressor in cancers of the digestive
system, where it has been connected to growth restriction by blocking
the G1/S cell cycle [85,87,89]. KLF4 overexpression has been shown to
promote the growth of CSCs in osteosarcoma and act as a
tumor-inducing gene in nasopharyngeal carcinoma [46]. Studies reveal
that KLF4 promotes the development of breast tumors, and 70% of
breast tumor cells have this TF upregulated [10,46]. In various tumor
cell lines, KLF4 has both oncogenic and tumor-suppressive properties.
KLF4 and the estrogen receptor (ER) directly interact with active p53,
and KLF4 regulates the expression of oncogenes connected to estrogen,
showing that lowering KLF4 in breast cancer cells may boost the pro­
liferative response to estrogen [84]. Bladder cancer cells (T24) depleted
of METTL3 (m6A axis, a core “writer” protein in bladder cancer) were
used to show that KLF4 is a downstream target of METTL3(RNA meth­
yltransferaseMETTL3) [90]. According to Nagata et al.a higher breast
cancer recurrence rate was linked to lower KLF4 expression [84]. Akaogi
et al. in 2009 reported that gene expression in breast cancer cells showed
reduced Klf4 expression as compared to healthy mammary gland cells
[92]. In breast cancer samples, it was possible to find the expression of
several factors that induce stem cells, including KLF4,c-MYC, NANOG,
OCT-4, and SOX-2. In contrast, KLF4 may have an inhibitory effect on
the spread and proliferation of this malignancy [92]. Recent research
showed that KLF4 knockdown in MCF-7 cells accelerated the prolifera­
tion of these cells in the presence of oestrogen [91,92]. Scientists
investigated the relationship between KLF4 and ERalpha (Estrogen re­
ceptor alpha) and discovered that KLF4 binds to ERalpha’s DNA-binding
region [93]. KLF4 prevents ERalpha from binding to promoter regions
that contain oestrogen response elements, which lowers the transcrip­
tion of ERalpha target genes [92]. According to past findings, p53
transcriptionally activates KLF4 following DNA damage [93]. It was also
demonstrated that p53 activation increased KLF4 expression, which
decreased ERalpha’s transcriptional activity. p53, ERalpha, and KLF4are
connected by a novel molecular network, as p53 and ERalpha both
contribute to cell proliferation and apoptosis [92,93]. Myeloma, leuke­
mia, prostate, breast, brain, head and neck, oral, and testicular cancers
have been reported to express KLF4 [94]. Additionally, the expression of
KLF4 can serve as a prognostic indicator for head and neck squamous
cell carcinoma and colon cancer[95–97]. Reports also suggest, nuclear
localization of KLF4 has been linked to a worse prognosis in oral and
nasopharyngeal malignancies [98] as well as an aggressive phenotype in
early-stage breast cancer [99,100]. Raf-kinase inhibitor protein prevents
KLF4 from directly interacting with Raf-kinase inhibitor protein via
controlling the KLF4/OCT-4/SOX-2 complex through the
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Seminars in Cancer Biology 88 (2023) 123–137
mitogen-activated protein kinase pathway [101]. KLF4 expression was
found to be positively connected with CD9/CD81 expression and
negatively related to downstream MAPKinase/JNK(c-Jun N-terminal
Kinase) signaling, implying that future therapies should target the
KLF4-CD9/CD81-Jnk pathway [91].
9. SALL1 (Spalt like transcription factor 1)
The SALL family of zinc finger domains includes the cysteine-
histidine-containing proteins SALL-1, SALL-2, SALL-3,and SALL-4.
SALL-1 is downregulated in malignancies like breast cancer, various
leukemias, and glioblastoma cells, which demonstrate its functions as a
tumor suppressor [102,103]. Sall1 overexpression also suppresses the
Wnt/-catenin signalling pathway by affecting the oncogene c-MYC and
Wnt downstream targets Cyclin D1 (Ccnd1) [10,104]. SALL-1 causes the
mesenchymal to epithelial transition by decreasing the mesenchymal
markers N-cadherin and vimentin while increasing the epithelial marker
E-cadherin [104]. Depending on the tissue, its genetic environment, the
control of epigenetic processes, and the particular SALL isoforms
involved, SALL proteins can either act as oncogenes or tumor suppres­
sors, or as proteins with a dual function [102]. Because isoforms differ in
structure, expression, and cellular localization, they may be in charge of
some of the various functions of several SALL proteins in cancer [102,
105]. For the purpose of preserving the pluripotency of embryonic stem
cells, it has been proposed that direct communication with the central
master regulators SOX-2, OCT-4, and SALL4 is essential [76]. Recent
studies have shown that SALL4 regulates several AT-rich genes that
encourage neuronal cell differentiation while maintaining the pluripo­
tent state in ESCs [105]. Leukemia, testicular, breast, colon, ovarian, and
liver malignancies have all been found to express SALL4 [106–108].
SALL4 expression has been investigated as a predictor for poor prognosis
in hepatocellular carcinoma, gliomas, and myelodysplastic syndromes
[109].
10. MYC
In stem cells, MYC regulates a wide range of both protein-coding and
non-coding genes as well as various biological functions like cell dif­
ferentiation, metabolism, and self-renewal [25]. A well-known tran­
scription factor called MYC promotes somatic cell proliferation
effectively, and this property, along with the finding that the majority of
human CSCs exhibit its deregulated expression, suggests that MYC might
make a potent therapeutic target. Human cancer cells frequently exhibit
deregulation of the oncogenic transcription factor c-MYC due to protein
stabilization, amplification, mutation, or over expression [110]. C-MYC
is a key transcriptional regulator in both malignancies and stem cells.
One of the most extensively researched oncogenes, C-MYC over­
expression, has been demonstrated to result in cancer in mouse models.
MYC is frequently deregulated in various human cancers and is among
the most efficient oncogenes for determining the phenotype of cell
transformation both in vitro and in vivo, and it helps in invasiveness as
well as in survival of CSCs [111]. Additionally, deactivating MYC in HCC
(Hepatocellular carcinoma) leads to a process by which stem cells
develop into biliary duct cells and hepatocytes, resulting in the forma­
tion of bile duct anatomy, which may be connected to the loss of feto­
protein, a tumor marker, and elevated levels of the hepatocyte markers
cytokeratin 8, cytokeratin 19, as well as liver stem cell markers [14,25].
Glioblastoma multiform stem cells also contain MYC, which promotes
invasion and cell proliferation while inhibiting apoptosis [112]. The
number of copies of the MYC gene was also found to be higher in human
and mouse prostate CSCs [25]. Reports demonstrate that when MYC is
deactivated in hepatocellular carcinoma, tumor cells begin to differen­
tiate and die in large numbers, but certain cells exhibit stem cell char­
acteristics and resume their ability to proliferate when MYC is activated
[113,114]. The liver tumors in a mouse model regressed after MYC was
inactivated, and the tumor dormancy continued for more than 8 months
A. Chaudhary et al.
[114]. The regulatory network of ovarian CSCs that suppresses genes
linked to adhesion and the cell cycle includes MYC. These TFs-based
therapies treat chemo resistance and recurrence of various cancers,
including ovarian cancer and liver cancer, taking into account the
therapeutic importance of a quiescent tumor enriched with CSCs [114].
Studies have shown that up to 70% of malignant cancers exhibit C-MYC
over expression, including leukemia and lymphoma as well as tumors of
the brain, pancreatic, breast, colon, renal, head, neck, prostate, testis,
and salivary gland[94,115,116]. In early HCC and uterine cervix cancer,
C-MYC expression has also been linked to a poor prognosis [107,117].
This information suggests that MYC, in combination with other factors,
promotes tumorigenesis in conjunction with other factors.
11. STAT3 (Signal transducer and activator of transcription 3)
STAT3 is widely expressed in gastric and colorectal CSCs, and it plays
a significant role in controlling a number of physiological activities,
including inflammation, proliferation, and invasion in CSCs [118–121].
High levels of STAT3 expression have been linked to the stemness and
invasive features of gastric CSCs [120,121]. Numerous studies suggest
that STAT3 activation is a marker of poor prognosis with regard to its
prognostic value [122–124]. One of the main oncogenic proteins
involved in proliferation, angiogenesis, invasion, and resistance to
chemotherapy and radiation [125]. Additionally, its inhibition reduces
the development of tumors, making it a desirable therapeutic target for
CRC(colorectal cancer) [119].
12. GLI1 (GLI family zinc finger 1)
The Sonic Hedgehog (SHH) pathway member GLI1 appears to be
crucial for the maintenance of cancer cells with stem-like characteristics
in various cancers like gastric cancer (GC) and colorectal cancer (CRC)
[126,127]. Its expression in GC is much higher in tissues where the
cancer has spread, and it is favorably linked with a more aggressive
tumor phenotype [126]. Additionally, it has been noted that GLI1 over
expression fosters a CSC phenotype by promoting cell motility, prolif­
eration, and resistance to treatment [128]. GLI1 is also crucial for CSC
traits associated with aggression and the metastatic spread of CRC cells,
which reduce survival.
13. SOX-9 (SRY transcription factor 9)
Developmental processes like chondrogenesis, neurogenesis, and
neural crest development are regulated by SOX-9 [129]. Furthermore, it
is required for the maintenance of stem cells and the determination of
cell fate in a variety of organs, including the digestive system, during
embryonic development and adulthood [130,131]. Its significance in GC
is still unclear; some studies support a link between reduced survival and
high SOX-9 expression, while others link a poor prognosis to low SOX-9
expression [132,133]. SOX-9 has also been linked to CRC due to its
oncogenic and tumor suppressor activities [134,135]. Previous research
suggests that this TF may be associated with a poor prognosis and may
regulate the CSC pool, which is the primary mechanism by which tumor
proliferation and progression are influenced [136,137].
14. YB-1
According to previous studies, the transcription factor YB-1 is mainly
linked to the stemness of stem cells in breast cancer and melanoma and
is necessary for keeping CSCs stem-like and turning tumor cells back into
CSCs [138]. It is confirmed that YB-1 is involved in the effective pres­
ervation of CSC properties [116]. According to prior research, YB-1 is
required for both the preservation of CSC stemness and the trans­
formation of CSCs from tumor cells [10,138]. The expression of GLP-1,
GINS1, p21, Notch2, and FZD-1 is increased by YB-1, which also sustains
CSCs’ stemness, inhibits apoptosis, and is needed for the activation and
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Seminars in Cancer Biology 88 (2023) 123–137
reversion of transformed cancer cells’ totipotency or pluripotency [10,
138,139]. YB-1 deletion may cause CSCs to differentiate, which would
reduce their capacity to form spheres and downregulate their stemness
genes. In contrast to published findings, YB-I rescue in YB-1 mutant CSCs
did not reprogramme the differentiated CSCs into stem cells [140,141].
It has been observed that the simultaneous presence of YB-1 and the
other four (SOX-2, OLIG1,POU3F2, and OCT-4) or five (SALL2,SOX-2,
Bmi-1, POU3F2, and OCT-4) transcription factors prevented the con­
version of YB-1-deleted melanoma stem cells or breast CSCs into CSCs
[138]. Therefore, YB-1 is necessary for the transformation of differen­
tiated cancer cells into totipotent or pluripotent states [138]. For better
understanding, a pictorial representation of various regulatory mecha­
nisms associated with these TFs in CSCs for the modulation of various
tumors is shown in Fig. 2, and their comprehensive role is summarized in
Table 1.
15. Biomedical perspective of CSCs
15.1. Targeting transcription factors for therapeutic anti-tumor strategies
in CSCs
Cancer therapies now focus on the TFs and signalling pathways that
control the maintenance and survival of CSCs. The OCT-4, SOX-2,
NANOG, KLF4, MYC, Wnt, Notch, and Hhsignalling pathways, as well as
the TGF-, JAK-STAT, PI3K, and NF-kβ signalling pathways, are the pri­
mary TFs and signalling pathways at the moment. When tumors are
developing in CSCs, these TFs and pathways frequently interact. Early
clinical trials for OCT-4, SOX-2, NANOG, Notch, and Hh pathway in­
hibitors have seen significant advancements; however, it has proven
challenging to target the Wnt pathway [25,142]. Fig. 3 depicts the
various therapeutic implications of targeting CSC transcription factors in
cancer therapy. Combination therapies may be the focus of future trials.
This field, however, is still in its early stages, and more research is
needed to produce some useful results.
15.1.1. Available therapeutic strategies for targeting the TF
The clinical potential of various transcription factors in CSCs is
promising. These TFs function as crucial carcinogenesis markers [143]
and as molecular switches that regulate the fate of CSC cells during the
course of cancer development [144]. A number of pluripotent tran­
scription factors, such as OCT-4, SOX-2, NANOG, KLF4, and MYC, as
well as some intracellular signalling pathways, like Wnt, NF-B, Notch,
Hh, JAK-STAT, PI3K/AKT/mTOR, TGF/Smad, and PPAR, are crucial
regulators of CSCs. Other regulatory extracellular factors, including
vascular niches, hypoxia, TAM, CAF, and exosomes, play a vital role in
CSC management. So to combat CSCs, researchers have also created
medications, vaccines, antibodies, and CAR-T (chimeric antigen recep­
tor T cell) cells that target these TFs, pathways, and exosomes [25,144].
Importantly, numerous CSC clinical trials have been conducted, and
they point to a bright future for cancer treatment [25]. A special class of
therapeutic targets, including blockage of differentiation and cell death
gene expression profiles, which are defining characteristics of malig­
nancies, is represented by mutated or deregulated transcription factors.
Numerous direct mechanisms, such as chromosomal translocations,
gene amplification or deletion, point mutations, and altered expression,
as well as indirect mechanisms involving non-coding DNA mutations
that affect transcription factor binding, result in altered transcription
factor activity in a variety of cancer types and can aid in the treatment of
CSCs [145]. Inhibition of transcription factor-cofactor protein-protein
interactions, inhibition of transcription factor-DNA binding, modulation
of transcription factor activity by altering levels of ubiquitylation and
subsequent proteasome degradation, as well as inhibition of transcrip­
tion factor expression regulators, are just a few methods that have been
demonstrated to target transcription factor activity in preclinical and, in
some cases, clinical studies. These breakthroughs in drug research have
a great chance of producing special compounds that will probably have
A. Chaudhary et al.
Fig. 2. A diagram illustrating how different CSC TFs are modulated in different cancer types. In order to promote stemness and tumor-propagating potential, these
transcription factors differentially regulate a network of regulatory mechanisms, which in turn drive the development of various types of cancer cells. The stemness of
CSCs is regulated by a number of molecular mechanisms that are brought about by these transcription factors.
an impact on how cancer is treated in the future [146]. It is possible to
suppress tumors by limiting the expression of CSC TFs or by sabotaging
the altered molecular pathways in CSCs [147]. Finally, the improved
efficacy of clinical trials combining CSC TF modulators with chemo­
therapy has already suggested that the functional redundancy of CSC
TFs may be overcome by combining TF modulators with or without
conventional cancer treatment. The use of cysteine-reactive inhibitors,
modulation of auto-inhibition, proteolysis targeting chimaeras (PRO­
TACs), targeting intrinsically disordered regions of transcription factors,
and combining transcription factor inhibitors with kinase inhibitors to
prevent the emergence of resistance are other recent developments in
the field of targeting transcription factors [148].
Over the last decade, cytotoxic T-lymphocyte-associated antigen 4
(CTLA4), programmed death 1 (PD-1), and programmed death receptor
ligand1 (PD-L1) have become more widely recognized [149,150]. In
patients suffering from advanced cancer, blocking TFshas produced sig­
nificant rates of response and demonstrated exceptional clinical out­
comes [142,151]. CSC-specific surface biomarkers are targeted by
monoclonal antibodies (mAbs), a new cancer therapy technology. To
improve accessibility and affordability of radioimmunotherapy for re­
fractory or recurring non-lymphoma Hodgkin’s (NHL), a phase II clinical
trial for Rituximab radioiodine replacement was carried out, in which 35
patients were involved, and showed a good response rate of 71% and a
total remission rate of 54%, with just 2 occurrences of grade IV hema­
tologic toxicity [25]. Chemokine receptors such as CXCR4 and SDF-1
have been discovered in the vast majority of cancer cells, particularly
CSCs. Plerixafor (AMD3100) is the most well-studied CXCR4 drug, and it
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Seminars in Cancer Biology 88 (2023) 123–137
works as a mobilizer of hematopoietic stem cells in NHL and patients with
multiple myeloma [152]. AMD3100 treatment for refractory or relapsed
AML (acute myeloid leukemia) resulted in complete remission in 46% of
patients, regardless of white count recovery, in phase I/II research [153,
154]. Musashi-1 (MSI1) and Musashi-2 (MSI2) are two RNA-binding
proteins (RBPs) that are increasingly being recognized as regulators of
numerous vital biological processes important for the development,
progression, and resistance to cancer treatment. These proteins support
the populations of CSCs and control metastasis, invasion, and the emer­
gence of more aggressive cancer traits, such as drug resistance. Despite
the fact that RBPs are challenging therapeutic targets, early attempts to
produce specific inhibitors for MSI are encouraging, and strategies based
on RNA interference to inhibit these proteins have shown encouraging
results in preclinical trials against CSCs[155]. Transmembrane 4 L-six
family member 1 (TM4SF1) has been shown to alter SOX-2 expression in a
Wnt/-catenin-dependent manner Furthermore, they reported that
TM4SF1 knockdown reduced the binding of c-MYC tothe SOX-2 gene
promoter by suppressing c-MYC production, preventing metastasis and
tumor growth in a xenograft mouse model [156]. CSC TFs, including
OCT-4, NANOG, and SOX-2, have been shown to be inhibited by the
vitamin B precursor fursultiamine TTFD (thiamine tetrahydrofurfuryl
disulfide), reducing their expression in esophageal carcinoma spheroids
and mouse xenografts [157]. Recently, it has been demonstrated that
circular RNA like Qki5-circZKSCAN1-FMRP-CCAR1targets theWnt­
signaling axis and could be a key therapeutic target for the treatment of
CSCs in hepatocellular carcinoma(HCC). Results from RNA immune
precipitation-sequencing (RIP-seq) and bioinformatics analysis revealed
A. Chaudhary et al. Seminars in Cancer Biology 88 (2023) 123–137

Table 1
A comprehensive summery of various TFs in the CSC population in different cancer types.The expression of TFs and an overview of different regulatory mechanisms
modulated by CSCs TFs in various tumors.
S. TFs Tumor types Expressional Phenotypes associated Molecular mechanisms Ref.
No analysis

1 OCT-4 Colorectal cancer Overexpression Progression of the cell cycle & Oct4/Tcl1/Akt1 pathway is activated. [47]
Apoptosis inhibition.
Cervical cancer Overexpression CSC-like phenotype. Upregulation of Akt1 pathway. [45]
Liver cancer Upregulation Increase neovascularization. Upregulation of epithelial-to- [50]
mesenchymal transition (EMT).
prostate cancer Upregulation Uncontrolled cell proliferation Downregulation of Ca2+channels, and [19,52]
CSC-like phenotype. upregulation of EMT, WNT/β,CATENIN,
and EGFR/PI3K/AKT pathways.
Squamous Cell Carcinoma of the Head and Upregulation Aggressive phenotype, inhibit Activation of Akt/mTORC1, and STAT3. [82]
Neck apoptosis.
Breast cancer Overexpression Increased tumor cell proliferation. Upregulation of WNT/ β-CATENIN, EMT [179,
and AMPK/mTOR pathways. 180]
Renal, Testis, Seminoma, Brain, Lung, Upregulation Self-renewal of stem cells and Activation of MAP4K4-Survivin, [181]
Bladder, Ovarian, and Leukemia preservation of pluripotency. downregulation of EGFR/Src/Akt and
BMP4 pathways.
2 SOX2 Gastric cancer Overexpression High proliferative and metastatic Upregulation of AKT signaling [159,
capacity, apoptosis and cell cycle 192,193]
arrest.
Squamous cell carcinoma Downregulation Decreased proliferation by cell Unknown [66]
cycle arrest.
Non-small cell lung cancer Overexpression Progression of the cell cycle & Activation of MAP kinase pathway and [182,
Apoptosis inhibition. down regulation of EGFR/Src/Akt 189]
pathways.
Breast cancer Overexpression Cell cycle progression, Apoptosis Upregulation of Wnt, EMT signaling and [183]
bypassing undifferentiated stat. downregulation of AMP kinase as well as
mTOR pathway
Colorectal Cancer Overexpression Proliferation, tumor burden, and Activation of BMP, MET,WNT/ [182,
high metastasis contribute to a poor β-CATENIN and downregulation of 185]
prognosis. mTOR
Neuroblastoma cells Overexpression Proliferation, tumor burden, Unknown [184]
metastasis, and a poor prognosis
Liver, Testis, and Prostate cancer. Upregulation Maintenance of pluripotency and Upregulation of EMT, WNT/ [73,178,
stem cell self-renewal. β-CATENIN,EGFR, PI3K and AKT 185,192,
pathways 193]
3 NANOG Hepatocellular carcinoma Elevated Cells invaded and induced EMT Activation of Akt/mTORC1, STAT3 [186]
expression with the high Vimentin/low E- pathway
Cadherin signature.
Breast cancer Elevated Anti-apoptotic proteins are Modulation of Hedgehog (Hh) & Notch [75]
expression upregulated and miR-21 levels are signaling pathways
increased.
Lung cancer Over expression Migration, colony formation, and Activation of MAP4K4 and AKT [61]
cycle progression. pathway.
Glioblastoma Over expression Proliferation, tumor burden, Modulation of Akt pathways. [187,
metastasis, and a poor prognosis. 188]
Head and Neck Squamous Cell Carcinoma Overexpression Aggressive phenotype, inhibit Unknown [24,77,
apoptosis. 187]
4 KLF-4 Colorectal Cancer Down regulation DNA synthesis has increased. Activation of the p38MAPK pathway [46]
Breast cancer Overexpression CSC-like phenotype of uncontrolled Activation of Wnt, Notch, TGF-β,and [87]
cell proliferation. Hedgehog pathways.
Nasopharyngeal carcinoma. Upregulation Increased tumor cell proliferation. Unknown [188]
Head and neck squamous cell carcinoma Upregulation Self-renewal of stem cells and Activation of MAP kinase pathway [190,
preservation of pluripotency. 191]
5 C-MYC Leukemia, Lymphoma, Myeloma, Brain, Overexpression Stem cell self-renewal. Modulation of Wnt-signaling pathways. [108,
Breast, Colon, Head and Neck, Pancreas, 115,116,
Prostate, Renal, Salivary-gland, testis 177]

that these circular RNAs exercised their inhibitory action by competi­
tively binding FMRP (Fragile X Messenger Ribonucleoprotein 1). This
prevented FMRP from binding to the mRNA for cell cycle and apoptosis
regulator 1 (CCAR1), which in turn reduced Wnt’s signaling ability to
activate transcription. Additionally, it was shown that the RNA-splicing
protein Quaking 5 was downregulated in HCC tissues and was respon­
sible for the decline in circZKSCAN1 [158]. Napabucasin is an orally
administered naturally occurring drug that induces apoptosis in CSCs and
inhibits CSC self-renewal in gastrointestinal malignancies by targeting
the transcription factors NANOG, STAT3, and -catenin signalling path­
ways in CSCs [159,160]. Ina Phase I/II clinical trial with
FOLFOX-bevacizumab or FOLFOX, patients reported that the soy-derived
compound genistein was well tolerated [116]. Similarly, genistein may
improve efficacy in the treatment of colorectal CSCs by targeting the
Wnt/-catenin and PI3K/AKT signalling pathways, both of which are
important regulators of normal intestinal growth and over activation
[161–164]. Additionally, it was shown that CD44 knockdown changed
breast CSCs into non-BCSCs with a drastic reduction in their
cancer-causing potential and also changed the cell cycle and expressional
profile of steaminess-related genes and TFsso that they were more com­
parable to those seen in non-BCSCs. Therefore, knockdown of CD44 is a
successful tactic for reducing BCSC stemness, which causes stemness loss
and increases susceptibility to chemotherapy or radiation [165]. Re­
searchers in recent years have also suggested that autophagy may be an
important element in the suppression of mTOR-mediated CSCs. Putative
esophageal CSCs may be removed with the help of mTOR pathway
stimulation. Additionally, the mTOR inhibitor Torin-1 promoted auto­
phagy activity, while the mTOR stimulator MHY1485 inhibited

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A. Chaudhary et al.
autophagy. In cells treated with the autophagy inhibitor hydroxy­
chloroquine, torin-1-mediated CSC induction was drastically decreased.
Esophageal cancer patient-derived organoids revealed a distinct
CD44 + /CD24-CSC population, and MHY1485 also decreased this pop­
ulation [166]. Thioridazine-loaded nanoparticles (Thz-HPPMc) could
greatly enhance the cancer-suppressing impact, while hyaluronic acid
(HA)-coated nanoparticles (HPMMc)could remain in the tumor site of
BALB/c nude mice for a longer time. These recent findings showed how
effective the multifunctional nanoparticle technology was at getting rid
of CSCs[167]. Additionally, after cisplatin treatment, a unique group of
likely target genes associated with the Hedgehog pathway and angio­
genesis genes that are crucial for controlling chemo-resistance and
self-renewability in triple negative breast cancer were only deregulated
in CSC-like cells. Researchers discovered that cisplatin is less harmful to
CSC-like cells than to parental cells through analyses of cellular and gene
expression. Understanding the role of deregulated potential target genes
produced by cisplatin in CSCs may help identify therapeutic targets for
cisplatin-resistant breast cancer [168]. The combination of CDDP
(cis-diamminedichloroplatinum) and a carbon ion laser offers a greater
ability to inhibit TN (triple negative) breast CSCs with heightened
apoptosis and severe, permanent DNA damage, as demonstrated by Sai
et al. in the year 2015. However, compared to X-ray paired with CDDP or
carbon ion beam alone, the combination of carbon ion beam and CDDP
dramatically reduced colony and spheroid formation and slowed cell
cycle progression (sub-G1 arrest). After combining CDDP with either an
X-ray or a carbon ion beam, the proportion of CSCs was higher and more
enriched [169,170]. Additionally, in their next report, they demonstrated
that, compared to an individual carbon ion or X-rays paired with gem­
citabine, a carbon ion beam has a higher potential to destroy pancreatic
CSCs through irreversible clustered DNA damage. Further, studies have
shown that the Chinese medicine beta-element can reduce the expression
of the genes for the cancer resistance proteins BCRP and P-glycoprotein
(P-gp), as well as the growth of BCSCs and the rate at which their spheres
form in the doxorubicin-resistant breast cancer cell line MCF-7/ADM
[171]. Recently, scientists also discovered that the growth of breast
cancer has been found to be inhibited by phytoestrogens, and more
recently, it has been revealed that they particularly inhibit breast CSCs.
Among the natural compounds investigated, phytoestrogens, especially
genistein, S-equol, naringenin, resveratrol, and pterostilbene,have
distinguished themselves as significant players with the capacity to
inhibit BCSCs through a variety of pathways [172]. In breast cancer cell
lines of non-hereditary origin, olaparib, a recognized inhibitor of poly
ADP ribose, an enzyme primarily involved in DNA repair, exhibits
anti-CSC action, possibly through activation of p-ERK [173].
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Seminars in Cancer Biology 88 (2023) 123–137
Fig. 3. Targeting transcription factors in CSCs
has therapeutic implications for cancer therapy.
A novel approach to cancer chemoprevention
and therapy may involve targeting CSCs TFs.
CSCs exhibit a variety of responses to survive
during and after therapy, such as EMT, self-
renewal, tumor environment, epigenetic,
quiescence modification, and targeting TFs that
modulate these pathways, which act as a game
changer in cancer therapeutics. TFs are known
to act on CSCs and the signalling pathways that
are involved in CSC self-renewal.
16. Challenges for targeting TFs in cancer therapeutics
Until now, such CSC-based therapies have only been performed in
the laboratory, but more research is being done to improve CSC
reprogramming and transcription factor-based therapies so that they
may be used safely, precisely, and successfully in clinical settings.
Numerous methods, such as exosome-directed CSC reprogramming,
small molecule, microRNA, and transcription factor-mediated cancer
stem cell reprogramming, have made great strides and shown great
innovation, making them more adaptable and practical in both pre-
clinical and clinical settings. Although clinical therapies on humans
remain technically and morally difficult, recent research suggests that a
number of non-coding RNAs (ncRNAs), including long non-coding RNAs
(lncRNAs) and microRNAs (miRNAs), may regulate the transcription
factors and downstream signalling pathways that CSCs activate to con­
trol their growth and replication [25]. Making links between these
findings may help in the creation of innovative treatments that can
target CSCs with specificity and lower cancer recurrence rates [174].
Although numerous clinical studies on these CSCs have been attempted
up to this point, many obstacles still need to be overcome before CSCs
can be effectively eliminated. Because of the vital role of CSCs in tumor
formation and poor patient outcomes, approaches to CSC-specific
treatment have emerged as a significant new strategy for prospective
cancer therapeutics. However, targeting the CSC microenvironment for
therapeutic targets remains a challenge now.
16.1. Potential solutions and future perspective
In order to develop treatments that may eliminate CSCs, we
comprehensively explore the effect of TFs and other components of
signaling pathways on cancer stemness in this paper, which will be able
to effectively detect and destroy these life-threatening CSCs. CSCs will
therefore be crucial as potential therapeutic targets in developing
cancer-controlling medications and improving patient clinical out­
comes. The discovery of innovative treatments for the complete elimi­
nation of CSCs will improve treatment modalities, and this will require
unlocking the biology of CSCs in carcinogenesis and metastasis. This
review helps in comprehending how harmful CSCs are and why man­
aging them is difficult. This paper covers a number of subjects that are
the subject of ongoing research. We focused on important transcrip­
tional regulators and signaling channels that are known to regulate CSC
behavior and interact in a variety of intricate ways. The transcriptional
networks that control CSCs are still not fully understood, and some
findings are controversial. In order to further understand and charac­
terize these regulatory processes, particularly through network analysis,
novel therapeutic targets may be found.
A. Chaudhary et al.
Small populations of CSCs create cellular heterogeneity, which is
linked to a long cell life span, relative quiescence, and treatment resis­
tance. This leads to cancer that is hard to treat, or "refractory." Due to
their ability to self-renew and resistance to drugs, CSCs allow cancer
cells to grow and change even after they have been treated with anti­
cancer drugs. There is not a single marker that can be used to recognize
all CSCs. In addition, cancer cells become more plastic during metastasis
in different types of malignancy. It is critical to comprehend the dif­
ferences between CSCs and normal stem cells. The above-mentioned TFs
in this review will definitely help us to separate, recognize, and examine
these populations within heterogeneous tumors. Examining these
characteristic TFs will aid in gene expression profiling, which offers
essential information that enables patient prognosis prediction. Clari­
fying CSC characteristics could help in the creation of cancer therapies
that take into account the tumor microenvironment and molecular
subtypes.
17. Discussion
The cancer disease continuously develops over time and has been
threatening human life for over a decade. As a result of the development
of numerous cancer treatment options, including chemotherapy, radia­
tion, and surgery, the incidence rate of cancer in women has largely
remained stable while slightly declining in men over the past ten years
(2006–2015), and the death rate from cancer has also decreased
(2007–2016) [14,25]. Conventional cancer therapy is only effective for
a small subset of malignant tumors due to metastasis, heterogeneity,
recurrence, resistance to radio/chemotherapy, and avoidance of
immunological surveillance. The existence of CSCs could be the cause of
all of these failures. By arresting in the G0 phase and forming new tu­
mors, CSCs can cause multidrug resistance, cancer relapse, and radiation
resistance [9139]. As a result, CSCs may be considered the most prom­
ising cancer treatment targets. With a better understanding of CSC
characteristics, tumor biology research has entered a new era. Under­
standing CSC biological properties is therefore crucial for tumor diag­
nosis and treatment. Since their discovery in leukemia in 1994, TF
targets for cancer modulation have been thought to be a promising
approach for cancer therapy [25]. There are transcriptional factors at
play in a variety of human disorders, including cancer, where they make
up about 20% of all oncogenes currently known [175,176]. Finding the
processes underlying drug resistance is a key objective in cancer
research, and new studies have linked CSCs to intrinsic resistance
models. The pathological self-renewal features of CSCs may be influ­
enced by overexpression of stem cell-specific transcription factors, while
surface molecules mediate intercellular interactions and their sur­
roundings. Other stemness-related indicators and mechanisms might
encourage the growth, development, and metastasis of cancer cells.
Understanding the stemness-related characteristics of cancers will not
only shed new light on the development of effective therapeutic stra­
tegies that specifically target these stemness-related characteristics but
will also contribute to our understanding of the underlying molecular
pathways in the pathogenesis of cancer.SOX-2, OCT-4, NANOG, MYC,
andKLF4 are just a few of the pluripotent transcription factors that
control the biological activity of CSCs. Numerous extracellular factors,
such as hypoxia, the vascular niche, tumor-associated macrophages,
exosomes, the extracellular matrix, cancer-associated mesenchymal
stem cells, and cancer-associated fibroblasts, have all been implicated in
the development of cancer. Several intracellular signalling pathways,
including Notch, Wnt, JAK-STAT, NF-kβ, Hedgehog, AKT/mammalian
target of rapamycin, and phosphoinositis, are also altered in cancer [25].
It makes sense that certain embryonic transcription factors would be
reactivated or re-expressed in CSCs [177]. As a result, these transcrip­
tion factors are crucial in controlling CSC development. Numerous nu­
clear signaling channels and transcription factors control how different
cell types develop tumors. Although these CSC TFs are typically well
established as tumor-promoting factors, the clinical implications of the
132
Seminars in Cancer Biology 88 (2023) 123–137
pluripotency of CSC transcription factors are getting more and more
complex. Both OCT-4 and SOX-2 exhibit real oncogenic behavior in
some cancers. Contrarily, CSCs appear to be physiologically quite
diverse within individual tumors as well as between various tumor
types. Even though pluripotency transcription factors are definitely
linked to cancer stemness, it does not look like they cover the whole
range of this stemness. Some CSCs preserve their stemness through
biological processes that are entirely dissimilar from pluripotency
stemness, occasionally even by activating signaling pathways that
encourage pluripotent stem cell development. Unexpected side effects
are regularly experienced when pluripotency transcription factors are
forced to express in cancer cells, including partial epigenetic normali­
zation, phenotypic reversion, and loss of the potential to initiate tumors.
The recurring tumorigenicity loss observed in induced pluripotent can­
cer cells may be due to the substantial dose dependence of reprogram­
ming pluripotency factors in addition to the extremely different
signaling contexts that are active in pluripotent and CSCs, respectively.
Finally, during pluripotency (cancer) reprogramming, numerous
signaling molecules have opposing cell-autonomous and
non-cell-autonomous effects. Therefore, the idea of CSC heterogeneity
provides the greatest justification for the impact of pluripotency tran­
scription factors in cancer [178]. However, it is still unclear what
transcriptional processes control the formation of CSCs that are tolerant
to harsh therapies. The in vivo therapeutic promise of TFs-based CSC
therapy will ultimately be confirmed in the future through testing on
mouse models for efficiency, safety, and specificity, as well as other
animal models. The in vivo dose and distribution, as well as the insta­
bility of CSCs and potential off-target consequences, provide challenges
for CSCs’ complete inhibition. CSC reprogramming obstacles are
currently preventing the promising strategy from being translated to
therapeutic applications. However, based on the constantly expanding
horizon in CSC biology, they appear to be solvable. The significance of
transcription factors in CSC biology, as well as their role in the devel­
opment of various cancers and drug resistance, is summarized in this
article. In order to better understand how transcriptional regulation of
different cancers affects the growth and development of a tumor as well
as its cell resistance to therapy, we looked at all of the major tran­
scriptional regulators. Our findings potentially lay the groundwork for
novel therapies for the removal of metastatic cancer and CSCs, and they
also contribute to a deeper understanding of the characteristics of CSCs
and suggest novel ways to use targeted therapy in cancer patients. There
have been many clinical trials on these CSCs, suggesting that the future
of cancer therapy is promising. However, before CSCs can be effectively
eliminated, a number of challenges must be surmounted.
18. Conclusion and future prospects
It is now obvious that the ability of CSCs to self-renew and metas­
tasize cannot be defeated by conventional chemotherapy. CSCs have
been recognized and isolated using a combination of transcription fac­
tors and their functional characteristics. Despite this development, there
is still a lack of precise CSC TFs to target this diverse cancer etiology.
This must be solved to create therapeutic approaches with more speci­
ficity and fewer adverse effects. In various pre-clinical models, targeting
CSC-associated oncogenes and signaling pathways, which were dis­
cussed above with small molecule inhibitors or therapeutic targets, led
to decreased CSC functionality and numbers, as well as tumor remission.
CSCs become resistant to traditional chemotherapeutics. However,
desensitizing CSCs to those same medications involves targeting various
TFs. The application of therapies, including regulation of CSC-specific
TFs, alone and along with traditional therapy will result in promising
and enhanced CSC targeting effects in various tumor types, as shown in
Fig. 4 graphical abstract. Anti-CSC strategies may be able to specifically
promote differentiation and prevent proliferation. Targeting CSCs by
altering these TFs and the tumor microenvironment has produced pos­
itive outcomes. TFs alone might not be effective enough to yield clinical
A. Chaudhary et al.
Fig. 4. Role of transcription factors in the therapeutic strategies of CSCs. CSCs is mainly targeted by different transcription factors that regulate various signaling
pathways, surface markers and gene regulations. These TFs also induces various inhibitors of ATP binding cassette transporters, immune evasions, and tumor
microenvironment which ultimately leads to the induction of CSCs apoptosis and thus inhibits tumor proliferation and self-renewal properties.
results. Consequently, combination therapy using both conventional and
anti-CSC drugs may be relevant in the future to enhance the efficacy of
treatment.
Acknowledgments
The work was supported by grant No. EMR/2017/004171 from DST-
SERB (Science and Engineering Research Board) India. The first author
thanks the Council for Scientific and Industrial Research (CSIR-UGC) for
providing fellowship.
Competing interests
The authors declare no competing interest.
Authors contribution
Rizwanul Haque contributed to the study’s conception and design.
Formal analysis and investigation were carried out by Archana
Chaudhary. Archana Chaudhary drafted the manuscript. RizwanulHa­
que and Syed Shadab Raza reviewed and edited the previous version of
the manuscript. All authors read and approved the final manuscript.
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