Biomedicine & Pharmacotherapy 141 (2021) 111873

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Biomedicine & Pharmacotherapy

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

The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma

Mohammad Malekan a, b, Mohammad Ali Ebrahimzadeh c, *, Fateme Sheida d
a
Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
b
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
c
Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
d
Student Research Committee, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

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

Keywords: Adaptation to the loss of O2 is regulated via the activity of hypoxia-inducible factors such as Hypoxia-Inducible
Hypoxia Factor-1 (HIF-1). HIF-1 acts as a main transcriptional mediator in the tissue hypoxia response that regulates over
HIF-1α 1000 genes related to low oxygen tension. The role of HIF-1α in oncogenic processes includes angiogenesis,
Melanoma
tumor metabolism, cell proliferation, and metastasis, which has been examined in various malignancies, such as
Signaling pathways
Diagnostic/prognostic biomarker
melanoma. Melanoma is accompanied by a high death rate and a cancer type whose incidence has risen over the
Melanoma treatment last decades. The linkage between O2 loss and melanogenesis had extensively studied over decades. Recent
studies revealed that HIF-1α contributes to melanoma progression via different signaling pathways such as PI3K/
Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, Wnt/β-catenin, Notch, and NF-κB. Also, various microRNAs (miRs)
are known to mediate the HIF-1α role in melanoma. Therefore, HIF-1α offers a diagnostic/prognostic biomarker
and a candidate for targeted therapy in melanoma.

1. Introduction (PHD1–3), which finally leads to their recognition by the von

In most solid tumors, adaptation to the reduction of O2 availability is
regulated via the activity of hypoxia-inducible factors such as Hypoxia-
Inducible Factor-1 (HIF-1) [1]. HIF-1 is a primary transcriptional
mediator in the tissue hypoxia response and the main regulator of O2
homeostasis that regulates over 1000 genes related to low oxygen ten­
sion [1,2]. Also, HIF-1 is a heterodimeric complex consisting of a
constitutively expressed beta subunit (HIF-1β, also known as the aryl
hydrocarbon receptor nuclear translocator [ARNT]) and an
oxygen-regulated alpha subunit (HIF-1α) [3]. These proteins are a
member of the basic helix-loop-helix–Per-ARNT-Sim (bHLH–PAS) fam­
ily. bHLH and PAS are needed for heterodimer arrangement between the
HIF-1β and HIF-1α subunits, and the basic downstream area affords
particular binding to the hormone response element (HRE) DNA chain
[4]. Two transcription stimulator domains, C-terminal (C-TAD) and N-
terminal (N-TAD), were identified. The C-TAD has been indicated to
interact with CREB-binding protein (CBP) and p300 co-activators to
activate gene transcription [3]. HIF-1α also includes an
oxygen-dependent degradation domain (ODDD) that mediates
oxygen-regulated stability [5]. Under normoxic conditions, critical key
proline residues HIFa subunits are hydroxylated by prolyl hydroxylases
Hippel-Lindau (VHL) protein their subsequent degradation by the pro­
teasome. In hypoxic conditions, PHDs activity is blocked, and VHL
cannot identify HIF-1α subunits, leading to its nuclear pathological ef­
fect [6]. Therefore, HIF-1α plays a role in angiogenesis mediated by
vascular endothelial growth factor (VEGF), cellular metabolism, tumor
invasion and metastasis, and cell survival [7–10].
Melanoma is caused by the malignant change melanocytes, which
typically occur in the skin but may rarely occur in the eye (uveal mel­
anoma) and mouth (oral melanoma); the pigment-producing cells lined
in the dermal-epidermal junction and the hair follicles [11–13]. Mela­
noma is accompanied by a high mortality rate and a cancer type whose
incidence has increased over the last decades. Only in the United States,
near 4.9 million adults have received skin cancer treatment from 2007 to
2011 [14,15].
Extensive studies were conducted on various aspects of the rela­
tionship between melanoma and HIF-1α [16,17]. For example, Martí­
nez-García et al. studied clinical staging and potential associations
between HIF-1α expressions and melanoma in the prospective multi­
center cohort study; they concluded that increasing of positively labeled
HIF-1α melanoma cells might have the potential of serving as a mela­
noma tumor prognosis and phenotype biomarker [8]. Hence, the present

* Corresponding author.
E-mail addresses: zadeh20@gmail.com, MA.Ebrahimzadeh@mazum.ac.ir (M.A. Ebrahimzadeh).

https://doi.org/10.1016/j.biopha.2021.111873
Received 26 May 2021; Received in revised form 25 June 2021; Accepted 28 June 2021
Available online 2 July 2021
0753-3322/© 2021 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
M. Malekan et al.
review aimed to address whether HIF-1α can serve as a diagnostic
/prognostic biomarker and a candidate for targeted therapy in
melanoma.
2. HIF-1α and signaling pathways
HIF-1α mediates the transcription of genes involved in different
processes, including stress adaptation, metabolism, apoptosis, tumor
growth, angiogenesis, and invasion [18]. Recent studies also revealed
that HIF-1α takes part in different signaling pathways such as
PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT, Wnt/β‑catenin,
Notch, and NF‑κB [19,20]. These pathways and associated complex
changes appear to affect tumor growth control, metabolism, motility,
and cell apoptosis in melanoma [21] (Fig. 1).
2.1. The PI3K/Akt/mTOR pathway
HIF-1α is located downstream of the mechanistic target of rapamycin
(mTOR) complex 1, which is individually regulated by the phosphati­
dylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway
[22]. Amplified signaling through PI3K/Akt, and its downstream target,
mTORC1, increases HIF-1α-dependent gene expression in several cancer
types, including melanoma [23,24].
The PI3K⁄Akt pathway activation in cancer is due mainly to muta­
tions in the tumor suppressor gene PTEN [25]. The PTEN gene produces
a phosphatase whose chief act is degeneration of PI3K products by
dephosphorylating phosphatidylinositol 3,4,5-trisphosphate and phos­
phatidylinositol 3,4-bisphosphate [26]. Loss of PTEN function increases
Fig. 1. HIF1 complex and related signaling pathways.
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Biomedicine & Pharmacotherapy 141 (2021) 111873
Akt phosphorylation and activity, leading to reduced apoptosis and
increased proliferation signaling [27,28]. A PTEN mutation has been
reported in about 30–50% of melanoma cell lines [29]. It seems to cause
amplification of the gene PI3K, located in chromosome 3q26, and en­
codes the p110a catalytic subunit of PI3K. This gene is frequently
amplified in several human cancers [30].
2.2. The RAS/RAF/MEK/ERK pathway
Some studies revealed that the MAPK/ERK pathway or RAS/RAF/
MEK/ERK pathway could regulate HIF-1α expression regulation [31,
32]. Specific growth factors activate RAS, which in turn stimulates
RAS/RAF/MEK/ERK kinase stream [33]. This signaling pathway even­
tually increases mRNA translation rate into HIF-1α protein [33,34].
Also, ERK phosphorylates the co-activator CBP/p300, so it raises
HIF-1α/p300 complex production. Interestingly, ERK affects the regu­
lation of HIF-1α synthesis and its transcriptional activation [33]. The
RAS/RAF/MEK/ERK signaling pathway is central to the pathogenesis of
melanoma. It is frequently activated by oncogenic mutations, such as
B-RAF, N-RAS, and mutations at upstream membrane receptors (e.g.,
KIT) [35]. Mutations in B-RAF seem to be the main common genetic
modification in 50–70% of melanoma cases [36,37]. N-RAS mutation is
the other major oncogenic cause in melanoma progression and happens
in about 20–25% of all cases [36,38]. Furthermore, MEK’s importance in
RAS/RAF/MEK/ERK pathway activation has been revealed in mela­
noma. Indeed, MEK acts as a mediator of melanoma oncogenesis and
plays a role in developing inhibiting apoptosis and cellular trans­
formation [39].
M. Malekan et al.
2.3. The Wnt/β-catenin pathway
HIF-1α has a role both downstream and upstream of the Wnt/β-cat­
enin signaling pathway; indeed, these have a mutual regulative function
[40,41]. The Wnt/β-catenin pathway is associated with the PI3K/Akt
pathway; also, β-catenin is involved in activating the RAS/RAF/ME­
K/ERK pathway [42,43]. So, Wnt/β-catenin can indirectly adjust HIF-1α
by PI3K/Akt and RAS/RAF/MEK/ERK pathways as an upstream
pathway.
Wu et al., like Liu et al. in their studies, expressed HIF-1α acts up­
stream of the Wnt/β-catenin pathway. These results showed that the loss
of O2 in the cell environment elevated the expression of HIF-1α, sub­
sequently activated the Wnt/β-catenin signaling pathway, and raised
β-catenin expression [40,41]. Microphthalmia Transcription Factor
(MITF) is the main determinant of both melanoma progression and
melanocyte development; Wnt/β-catenin signaling regulates the
expression of MITF. So this pathway has been promoted in the patho­
genesis of both malignant melanomas and benign melanocytic nevi [44].
Fig. 2. Representative Hypoxia/HIF-1α regulatory genes and their effects on melanoma progression.
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Biomedicine & Pharmacotherapy 141 (2021) 111873
Ploper et al. showed that MITF stabilization made a rise in multi­
vesicular body biosynthesis, which in turn enhanced Wnt signaling,
resulting in a positive-feedback loop that may account for melanoma
proliferative stages [45].
2.4. The JAK/STAT pathway
The signal transducer and activator of transcription (STAT) family
proteins consist of seven transcription factors, and the anus kinase (JAK)
family has four members [46,47]. They are involved in the activation of
target genes in response to growth factors and cytokines [47].
Recent studies have been shown that hypoxia activates the JAK⁄
STAT signaling pathway in several tumor cell lines and animal models
via HIF-1α [48,49]. This pathway has also been indicated to work with
HIF1 in the activation of VEGF and haptoglobin gene transcription
during hypoxia [50]. Multiple mechanisms have been inferred to
mediate STAT’s effect on cancer formation, such as STAT impact on
immune surveillance and control of apoptosis, growth factor signaling,
M. Malekan et al.
and angiogenesis; all are likely also to impact melanoma [51,52].
Guenterberg et al. showed that IL-29 is expressed on melanoma cell
lines and activation with this cytokine led to the expression of multiple
genes and an increase in apoptosis via Jak-STAT signal transduction
[53]. Another study suggests an increase of JAK/STAT signaling in
melanoma tumor cell lines by genetic inhibition of the negative regu­
lator PTPN2 potentiated IFN-γ response in vivo and in vitro. Hence this
pathway may be a target to develop immunotherapy efficacy [54].
3. Hypoxia/HIF-1α in melanoma progression
The decreased availability of oxygen, hypoxia, is a major feature of
solid tumors, which increases poor clinical outcomes in cancer patients
[55]. Indeed, massive tumor-cell proliferation separates cells from the
vasculature, then oxygen and nutrients shall be inadequate for the
rapidly growing tumor cells [56]. Developmental responses to hypoxia
are mainly regulated by HIF- 1α that is encoded by the HIF1A gene [57].
Hypoxia activates HIF-1α that promotes tumor growth by regulating the
expression of genes involved in angiogenesis, metabolism, cell prolif­
eration, metastasis, and other biological mechanisms; these processes
finally lead to melanoma progression [58,59] (Fig. 2).
3.1. Angiogenesis
Angiogenesis is the new blood vessel organization from preexisting
ones and is required for tumor progression [60]. Angiogenic factors such
as vascular endothelial growth factor (VEGF), Nitric oxide synthase
(NOS), and transforming growth factor (TGF) activate tumor angio­
genesis [61–63]. The major regulator of angiogenesis is VEGF and its
receptors, which are mainly associated with HIF-1α protein expression
[64]. HIF-1α is translocated into the nucleus under hypoxic conditions,
activating a wide array of downstream genes, including VEGF [65].
In melanoma, vascular formation is highly seen, and there are
extensive studies that supporting HIF-1α and angiogenesis for the tumor
progression and treatment of melanoma [66–68]. Simonetti et al. con­
ducted a study to recognize the correlation between angiogenesis and
hypoxia in primary oral melanoma development. They used immuno­
staining markers of CD34, VEGF, and HIF-1α in 16 malignant primary
melanomas patients. It was observed that there are positive correlations
between VEGF and HIF-1α expression in invasive front vessels. Finally,
they concluded that patients survival is significantly associated with
high HIF-1α expression and angiogenic activity of endothelial VEGF
[69].
3.2. Metabolism
It has been indicated that cancer cells have different metabolism
compared to normal cells; perhaps the most prominent variation in
cancer cells is aerobic glycolysis or the Warburg effect [70]. In this
condition, glucose metabolism is mainly fermentative rather than res­
piratory, with raised lactate production, even when enough O2 present
to support mitochondrial function [71]. Indeed, switching to aerobic
glycolysis is a critical adaptive response to hypoxia. Glycolysis has low
efficiency in ATP production than mitochondrial respiration; therefore,
the high glycolysis in the tumor for energy production causes cancer
cells to consume more glucose [71,72].
HIF-1α is the main transcription factor for the induction of many
genes encoding glycolytic enzymes and glucose transporters, allowing
hypoxic tumor cells to take up more glucose efficiently [72]. The
up-regulation of glucose transporter proteins 1 and 3 (GLUT1 and
GLUT3) is a critical characteristic in cancer cells regulated by HIF-1α.
GLUT transporter’s main cellular role is to facilitate glucose entry into
the cell [73].
Moreover, HIF-1α can up-regulate hexokinase 1 and 2 levels (HK1
and HK2) in tumor cells. HK is the early glycolytic enzyme that enables
glucose conversion to glucose-6-phosphate in cancer cells, hence
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Biomedicine & Pharmacotherapy 141 (2021) 111873
committing the glucose to the glycolytic cycle [74,75]. HIF-1α also in­
duces transcription of pyruvate dehydrogenase kinase 1 (PDK1). PDK1
blocks the transformation of pyruvate to the acetyl CoA via inhibiting
pyruvate dehydrogenase activity [75]. Multiple studies have examined
the metabolism of melanoma cancer cells under hypoxia conditions [76,
77].
Scott et al. have shown that all melanoma cell lines produce more
lactate and utilize more glucose than normal melanocytes [76]. In
another study, Koch and his colleagues conducted a study that widely
investigated the characterization of glycolysis-related gene expression in
malignant melanoma. They observed significant up-regulation of HIF-1α
target genes GLUT1, HK2, and lactate dehydrogenase-A (LDH-A) in
melanoma cell lines under hypoxic conditions. Moreover, GLUT1
expression was significantly elevated in metastatic and BRAF-V600E
mutated melanoma cell lines. GLUT1 expression in melanoma tissue
samples associated significantly with HK1, LDH-A, and Mono­
carboxylate transporter 1 (MCT1) expression, which confirmed a
glycolytic phenotype of melanoma cell lines [77].
3.3. Cell proliferation or cell death
Hypoxia induces a chain of effects that lead to tumor cell prolifera­
tion; however, in severe conditions, hypoxia can also help cell death by
the presence in tumors of a central necrotic zone [78]. In fact, HIF-1α
affects cell proliferation and death by regulating the expression of
cellular myelocytomatosis (C-MYC), insulin-like growth factor 2 (IGF2),
and other regulators of the cell cycle and death pathways [59]. Highly
variable levels of hypoxia can be expected to accompany the dynamics
of tumor mass spatiotemporal growth so that a multitude of tumor cell
responses are represented [78]. C-MYC is a human oncogene that is
commonly altered in many forms of cancer, including melanoma [79,
80]. C-MYC overexpression in cancer cells can increase the HIF-1α
expression and that of VEGF.
Moreover, It is determined that C-MYC sets HIF-1α at the post-
transcriptional level. C-MYC is also essential for regulating angiogen­
esis and contributes to tumor proliferation [79]. Mouriaux et al. con­
ducted a retrospective analysis on uveal melanoma tumors from 88
patients. They concluded that increased HIF-1α expression correlated
with cell proliferation and vascular markers CD31 and VEGF-A expres­
sion [81]. Several studies stated that the HIF-1α induced BH3-only
protein family of cell death factors via BNIP3 and BNIP3L genes in
hypoxia conditions [78,82,83]. Wu et al. showed that α-melanocyte
stimulating hormone (α-MSH) stimulated the HIF-1α signaling, and then
the expression of BNIP3/BNIP3L is induced, thereby promoting the
apoptosis and autophagy in melanoma cells [84].
3.4. Metastasis
Activation of the HIF-1α is one of the most prominent mechanisms
that increase metastasis and enhances tumor aggressiveness [85].
HIF-1α regulates the expression of genes encoding metastasis, including
fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), urokinase plasmin­
ogen activator receptor (uPAR), epithelial-mesenchymal transition
(EMT) inducers, and other components involved in the invasion
[86–88]. Lin et al. expressed that HIF-1α-related pathways such as
MAPK, NF-κB, and PI3K/AKT mediated the expression of EMT genes that
initiated the metastatic cascade of melanoma. For example, the
HIF-1α/NF-κB axis directly regulates EMT through the gene product
transcription. Then, this axis indirectly acts through the transcriptional
up-regulation of the metastasis inducer Snail [89].
In another study, Li et al. reasoned that luteolin inhibited melanoma
cell migration and invasion by inhibiting the HIF-1α/VEGF signaling
pathway. Luteolin effectively repressed EMT by decreased N-cadherin
and vimentin expression and increased E-cadherin in mRNA and protein
levels. Besides, they stated that luteolin induces its anti-metastatic ac­
tion by reducing the p-Akt, HIF-1α, VEGF-A, p- VEGFR-2, MMP-2 MMP-
M. Malekan et al. Biomedicine & Pharmacotherapy 141 (2021) 111873

9 proteins expression [90]. 5. HIF-1α as a diagnostic/prognostic biomarker in melanoma

4. MicroRNAs as mediators of the HIF-1α role in melanoma
Extensive studies have examined the relationship between micro­
RNAs (miRs) and HIF-1α in melanoma. Some miRs have inhibitory ef­
fects on HIF-1α expression in melanoma tumors; however, there are
miRs that increase HIF-1α expression in melanogenesis [10,91–94].
Hwang et al. investigate the expression of four miRs, including miR-210,
miR-218, miR-224, and miR-452, in the human melanoma cell lines.
They determined that decreased expression of these miRs in the TGFβ1
pathway-expressing melanoma cells restricted the cell cycle; these re­
sults suggested that HIF-1α may regulate the biological behavior of the
TGF-β1 pathway-expressing melanoma cells and the expression of some
genes through miR-210, miR-218, miR-224, and miR-452 [95].
Another study revealed that miR-652/HIF-1α axis promoted migra­
tion and proliferation of MUM-2B and MEL270 uveal melanoma cells;
indeed, miR-652 promoted HIF-1α signaling via suppression of Ho­
meobox A9 (HOXA9) [96]. Chen et al. showed that HIF-1α was the
miR-138 direct target, and miR-138 negatively regulated the HIF-1α
protein expression in WM451 melanoma cells. HIF-1α also has an
important role in glycolysis; upregulation of miR-138 notably inhibited
the glycolysis level. All in all, they concluded miR-138 suppressed the
invasion, proliferation, and glycolysis in malignant melanoma cells by
targeting HIF‑1α [97]. Table 1 summarizes studies examining miRs and
HIF-1α relationships in melanoma based on a systematic search in
PUBMED and SCOPUS.
HIF-1α has continuously been remarked as one of the diagnostic/
prognostic biomarkers for various cancers, including colorectal cancer
[103], pancreatic cancer [104], glioblastoma [105], as well as mela­
noma [106,107]. Nevertheless, there are few studies about the diag­
nostic/prognostic marker role of HIF-1α in melanoma. Fridman et al. did
a study on morphological characteristics of B16 rats melanoma pro­
gression with a high and low resistance to hypoxia. They expressed that
it is necessary to consider hypoxia and hypoxia-inducible factors during
exploring new prognostic markers for melanoma progression in mice
[108].
Another study showed that HIF-1α target genes, including GLUT1,
HK2, and LDH-A, are up-regulated under hypoxic conditions. On the
other hand, Cyclin D1 expression was associated with GLUT1, HK1,
LDH-A in human melanoma tissue samples. They stated that Cyclin D1
expression level could be a prognostic marker for melanoma patients’
outcomes [77]. Xia et al. indicated that miR-652/HIF-1α/HOXA9 axis
could be a useful biomarker for uveal melanoma patients’ prognosis;
they stated that miR-652 enhances HIF-1α signaling via inhibition of
HOXA9. Also, HOXA9 silencing weakens the inhibitor function of
miR-652, and then cell proliferation rate and migration potential are
decreased in uveal melanoma cells [96].
6. Targeting HIF-1α in melanoma treatment
Extensive studies are conducted on the potential of HIF-1α and

Table 1
Summary of studies that investigated miRs associated with HIF-1α.
MicroRNA Relationship Function Target gene / Cell type (s) Ref.
with HIF-1α Signaling pathway

miR-210 Up-regulated by Decreased expression of these four miRNAs in TGFβ1 pathway- Bnip3 / TGFβ1 0380-MMU, UACC-3093, 0620- [95]
miR-218 HIF-1α expressing melanoma cells lines restricts the cell cycle, while their pathway LNA, 0708-LND, and UACC-647
miR-224 overexpression in melanoma cells enhances the expression of the
miR-452 hypoxic response gene Bnip3
miR-33a Inhibits HIF-1α Overexpression of miR-33a significantly inhibited melanoma PDK3 / miR-33a/HIF- A375, WM451 and SK-MEL-1 [93]
tumorigenesis by inhibition of HIF-1α/PDK3 1α signaling axis
miR-652 Promotes HIF-1α Overexpression of miR-652 directly inhibited HOXA9 expression and miR-652/HOXA9/ MUM-2B and MEL270 [96]
led to the activation of the HIF-1 signaling pathway HIF-1 axis
miR-18b Inhibits HIF-1α miR-18b inhibits the growth of melanoma cells by directly targeting miR-18b/HIF-1α axis B16 and A375 [94]
HIF-1α in vitro and in vivo
miR-33a-5p Inhibits HIF-1α miR-33a-5p acts as a tumor suppressor by inhibiting HIF-1α-mediated Glycolysis / miR-33a- A375, WM35, WM451, and SK- [98]
glycolysis 5p/ HIF-1α axis MEL-1
miR-33a-3p Inhibits HIF-1α miR-33a-3p enhanced sensitivity to radiotherapy in melanoma cells Glycolysis / miR-33a- WM35, WM451, and A375 [99]
via repression of the hypoxia-inducible factor 1α (HIF-1α)/lactate 3p/ HIF-1α axis
dehydrogenase A glycolysis axis. Moreover, HIF-1α, after the
identification of the miR-33a-3p promoter region, via histone
deacetylase 2 reduces the expression of miR-33a-3p, in this regard,
creates a negative feedback loop is created.
miR-33b Inhibits HIF-1α Expression of HIF-1α negatively regulated by miR-33b at the post- Glycolysis / miR- WM35, WM451 and SK-MEL-1 [92]
transcriptional level in melanoma cells. Overexpression of HIF-1α 33b/HIF-1α axis
reverse the inhibitory effect of miR-33b on the proliferation and
glycolysis in melanoma cells.
miR-138 Inhibits HIF-1α miRNA-138 directly targeted HIF1α, and miRNA-138 overexpression miR-138/ HIF-1α WM35, A375 melanoma cells and [100]
or HIF1α inhibition significantly repressed the growth and metastasis HEK293
of melanoma in vivo
miR‑138 Inhibits HIF-1α miR-138 seems to inhibit proliferation, invasion, and glycolysis in Glycolysis / miR- WM451 melanoma cells and [97]
melanoma cells, potentially via the direct inhibition of HIF-1α. 138/ HIF-1α axis normal human melanocyte cell
line
miR-155 Inhibits HIF-1α The level of HIF-1α is a direct target of miR-155, and It is indicated miR-155/HIF-1α B16-F10 melanoma cells [101]
that miR-155 deficiency promoted melanoma growth
miR-211 Inhibits HIF-1α Expression of miR-211 reduced HIF-1α protein levels and decreased PDK4 / miR-211/ A375, and WM1552C, as well as [91]
cell growth during hypoxia. HIF-1α protein loss was associated with HIF-1α axis the human epidermal melanocyte
the downregulation of miR-211 target the gene PDK4. cell line HEM-l
miR-210 Inhibits HIF-1α The highest level of miR-210 expression caused HIF-1α gene NADH/NAD+/ miR- SK-MEL-30 [10]
silencing; their results suggest the potential use of targeted HIF- 1α 210/ HIF-1α
and miR-210 respectively gene silencing in the therapy of malignant
melanoma
miR‑199a‑5p Inhibits HIF-1α Overexpression of miR‑199a‑5p repressed cell proliferation and miR‑199a‑5p/HIF-1α B16 and HME1 melanoma cell [102]
arrested the cell cycle in the G1 phase; it also significantly lines
downregulated the expression of HIF-1α in vivo.

5
M. Malekan et al.
related target genes in melanoma treatment. One approach is sup­
pressing tumors via miRs, that HIF-1α regulates in tumor hypoxia con­
ditions [109,110]. MiR-33a [93], miR-33b [92], miR‑199a‑5p [102],
miR-138 [97,100], and miR-18b [94] are miRs investigated as a sup­
pressor of melanoma as presented in Table 1.
Moreover, other approaches based on using the HIF-1α oncogenic
mechanisms are recommended and practiced in various studies on
melanoma tumors inhibiting and curing melanoma patients [111–113].
Park et al. studied vanillin (an organic phenolic aldehyde) as an anti-
metastatic and anti-cancer intervention in malignant melanoma cells.
They observed that vanillin down-regulates the expression of HIF-1α
protein and related HIF-1α target genes, including FN1, LOXL2, and
uPAR, which are involved in melanoma metastasis. Indeed, the vanillin
exerted its anti-metastatic and anti-cancer effect via the STAT3/HIF-1α
signaling pathway under hypoxic conditions [111]. Liu et al. conducted
a study targeting HIF-1α through transferrin receptor-mediated endo­
cytosis with the transferrin–polyethylenimine–short-hairpin RNA
(Tf-PEI-shRNA) complex for malignant melanoma repressing. They also
reported that their method to target HIF-1α holds promise as a clinical
gene therapy approach for malignant melanoma [112]. Another study
indicated that HIF- 1a negatively sets TET2 gene and protein expression;
therapeutic interventions to inhibit HIF-1α via adjuvant ascorbic acid
may promote a critical tumor’s reexpression suppressor genes in ma­
lignant melanoma cells [114].
Zheng and his colleagues showed that the knockdown of F-box only
protein 22 (FBXO22) repressed angiogenesis, cell migration, and inva­
sion by the HIF-1α/VEGF pathway in melanoma cell lines [115]. Kluza
et al. presented a preclinical validation of the HIF-1α and pyruvate de­
hydrogenase kinase-3 (PDK3) pathway as a new therapeutic interven­
tion in metastatic melanoma. They declared that dichloroacetate (DCA)
presents its antitumor effects via blockades of the HIF-1a pathway, ul­
timately reduce glycolysis and promoted mitochondrial respiration via a
specific reduction in the expression of PDK3 [116]. Li et al. offered
luteolin as a possible therapeutic candidate in melanoma, which acted
through the HIF-1α/VEGF signaling pathway and EMT markers [90].
Licarete et al. conducted a study on B16.F10 murine melanoma cells.
They handled simvastatin cytotoxicity to target HIF‑1α for anti-cancer
strategies against melanoma [117]. Spinella et al. presented an endo­
thelin B receptor antagonist, which prevented invasive behavior of
melanomas via HIF-1α [118]. Smolarczyk et al. introduced anti-vascular
agents with HIF-1α inhibitors, which repress melanoma tumors [119].
Zhao et al. determined that selective inhibition of HIF-1α and glycolysis
regulated by pyruvate dehydrogenase kinase 1 (PDK1) through
2-methoxyestradiol (2-MeOE2) enhances radio-sensitivity of melanoma
cells [120].
Also, Shah et al. introduced vitamin K3 (menadione) as an E3
ubiquitin ligase Siah2 inhibitor leading to melanoma tumorigenesis
blockage. They declared that Siah2 ubiquitin ligase regulates hypoxia
response and some related pathways such as MAPK. It was showed that
menadione significantly suppressed the growth of melanoma xenograft
tumors [121]. Martí-Díaz et al. used acriflavine as a potent inhibitor of
HIF-1α dimerization to examine its potential in melanoma treatment.
They found that acriflavine via inhibiting the HIF-1α/PDK1 axis and
blockage of necessary adaptive mechanisms for melanoma cell survival
under metabolic stress could be a new promising targeted therapy
approach for melanoma [122]. Furthermore, Indian researchers showed
that Cinnamaldehyde suppressed melanoma cell angiogenesis and
metastasis induced by hypoxia. Indeed, Cinnamaldehyde acts through
targeting PI3/Akt/mTOR pathway, leading to reduction of HIF-1α pro­
tein content [123].
A group of Malaysian researchers preclinically carried out a study to
determine whether Phyllanthus (P. amarus, P. niruri, P. urinaria, and
P. watsonii) could be a medication for skin melanoma treatment or not.
Interestingly, they observed that cancer-related progressive pathways
like NFκB, MAPK/ERK, hypoxia suppressed by down-regulation of pan-
Ras, c-Raf, RSK, Akt, and HIF-1α. They concluded that these compounds
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Biomedicine & Pharmacotherapy 141 (2021) 111873
showed encouraging inhibitive effects on melanoma cell migration and
metastasis, proliferation, glycogenesis and glycolysis, protein synthesis,
and energy metabolism. This study provided a preclinical treatment
strategy related to HIF-1α and its signaling pathways [124].
7. Concluding remarks and future directions
This review showed that HIF-1α takes part in different signaling
pathways such as PI3K/Akt/mTOR, RAS/RAF/MEK/ERK, JAK/STAT,
Wnt/β‑catenin. These pathways are associated with melanoma angio­
genesis, metabolism, cell proliferation, metastasis. Also, it is pointed
different miRNAs engage in HIF-1α-related axes. HIF-1α not only can be
a diagnostic/prognostic biomarker for melanoma patients but also a
novel therapeutic approach. However, a lot remains to be done to clarify
the mechanisms associated with and the implication for treatment and
melanoma diagnosis.
More research into the relevance of HIF-1α induced gene products as
markers of prognosis should start and develop. The expansion of anti-
angiogenic, anti-growth, anti-glycolysis, and anti-metastasis agents
based on HIF-1α with potential as a melanoma therapy has led the way
in demonstrating that the tumors’ hypoxic response can be targeted.
Financial disclosure
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
All authors actively contributed to writing the manuscript. Also, M.
M. helped draw figures for the project, and M. A. E. developed the
theoretical framework and contributed the final version of the
manuscript.
Conflict of interest statement
There is no actual or potential conflict of interest and our funding
source has no role in study design, in the collection, analysis and
interpretation of data, in the writing of the report, and in the decision to
submit the paper for publication.
Acknowledgments
None to declare.
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