low levels of SIRT6 are associated with poorpatient outcomes. These findings have clini-cal implications: SIRT6 expression couldserve as a biomarker for cancer prognosis,and SIRT6-activating compounds might bepowerful drugs. Indeed, several features of SIRT6 make it an especially promising phar-macological target. In particular, it is a highly selective enzyme that removes acetyl groupsfrom only a few proteins
, and its known
cellular functions are all consistent with benefi-cial effects in the context of cancer. Therapeuticactivation of SIRT6 might therefore have fewer
unwanted effects than modulating the activity of more promiscuous enzymes.
There is growing evidence that tumour sup-pressors often control several aspects of cancer
biology, and SIRT6 is no exception
It prevents chromosome breakage and abnor-
mal rejoining, and promotes DNA repair —activities that protect against mutations thatcan fuel tumour progression. It also regulatesgene-expression programs that have roles in
cancer. For instance, it prevents excessive gene
activation by NF-κB — a transcription factorthat promotes cell proliferation, resistance tocell-death signals, and metabolic and inflam-
matory processes that favour tumour initiationand growth. Sebastián
report yet another
tumour-suppressing effect of SIRT6: it limitsthe expression of genes that are involved inprotein synthesis and which are activated by
oncogene to support tumour growth.
Despite these and other possible tumour-suppressive mechanisms of SIRT6 action, theresearchers propose that it is the metabolicrewiring triggered by inactivation of thisprotein that is essential to making cells can-cerous. Indeed, SIRT6 is known to opposegene activation by HIF1, a transcription fac-tor that activates key enzymes of glycolysisand increases glucose uptake into cells. The
authors also show that reversing the increased
glycolysis in cancerous SIRT6-deficient cells
— by inactivating a central glycolytic enzyme
or by reintroducing SIRT6 — reduces the cells’
Sebastián and colleagues further pro-pose that even without any other oncogenic
changes, increased glycolytic metabolism due
to SIRT6 loss is sufficient for tumour initia-tion. That a single genetic change is enoughto transform normal cells into tumour cellswould be a remarkable exception to the rulethat combined deregulation of several path-
ways is required for oncogenic transformation.
If proven, this could indicate that metabolicchange associated with SIRT6 loss suppliesa more powerful oncogenic drive than most
other known cancer-promoting mutations.
Alternatively, other effects of SIRT6 loss on
tumour-suppressive pathways could favour
early steps in cancer development. Future work
should ask how various functions of SIRT6contribute to cancer prevention, and how
these intersect with cellular metabolic control.
SIRT6. If increasing the amount or activity of
SIRT6 can indeed reduce the tumorigenicity of
cells transformed by other oncogenic manipu-
lations, strategies involving SIRT6 activation
could eventually be widely used for tumour sup-pression. It is noteworthy that SIRT6 attenuates
ageing-related cellular processes, and increas-ing its activity in mice can extend lifespan
So SIRT6 activation might not only provide an
anticancer strategy, but also serve as a preven-
tive medical intervention throughout life.
Katrin F. Chua
are in theDivision of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine; and at the VA Palo Alto Health CareSystem, Geriatric Research, Education and Clinical Center, Palo Alto, California 94304, USA.e-mail: firstname.lastname@example.org
1. Levine, A. J. & Puzio-Kuter, A. M.
1340–1344 (2010).2. Sebastián, C.
et al. Cell
1185–1199 (2012).3. Tennen, R. I. & Chua, K. F.
Trends Biochem. Sci.
39–46 (2011).4. Hanahan, D. & Weinberg, R. A.
646–674(2011).5. Hahn, W. C.
et al. Nature
464–468 (1999).6. Min, L.
et al. Nature Cell Biol.
1203–1211 (2012).7. Xiao, C.
et al. J. Biol. Chem.
41903–41913 (2012).8. Kanfi, Y.
et al. Nature
Erase for a new start
T oins gula gn xssion by moving mhyl gous fom DNAbass. This aciviy may b a faciliaing s in uning on h cll-divisionahway ha oducs sm and gg clls.See Letter p.443
SYLVAIN GUIBERT & MICHAEL WEBER
eiosis is a type of cell division thatis a key feature of sexual reproduc-tion. Meiotic division of germ cells
produces sperm and egg cells, which have only one copy of each chromosome and which fuse
during fertilization to create a new organismwith two copies of the genetic material. This
highly orchestrated process requires the activa-
tion of a specific set of meiotic genes, but how
these genes are activated at the right time and
in the right place is poorly understood. On
page 443 of this issue, Yamaguchi
reportthat Tet1, a member of the recently discovered
Tet protein family, is required for the activa-tion of meiotic genes in mouse egg cells. This
is exciting because Tet proteins are involved inerasing DNA epi genetic marks, suggesting that
this is a crucial mechanism in meiosis.
Epigenetic modifications are chemical orstructural changes to DNA or DNA-boundproteins that modulate gene expression with-out changing the DNA sequence. One com-mon epigenetic mark is the addition of a
methyl group to cytosine, one of the four mainDNA bases, thereby creating 5-methylcytosine.
In mammals, this methylation modifies theaccessibility of the DNA molecule and medi-ates long-lasting silencing of gene expressionand of parasitic mobile elements (regions of
DNA that can move within the genome)
methylation is essential for the survival of the
embryo, and its occurrence is dynamically
regulated during development
Members of the Tet (ten–eleven transloca-tion) protein family have been implicated inremoving this methylation mark from DNA— the proteins can oxidize 5-methylcytosineto form 5-hydroxymethylcytosine, 5-formyl-cytosine and 5-carboxylcytosine, which arepotential intermediates of demethylation
.This discovery was groundbreaking, becausethe mechanisms of DNA demethylation inmammals were a mystery for decades, andit prompted intensive research on the threemammalian Tet proteins (Tet1–3). We now know that Tet3 is expressed in oocytes (eggcells) and is required for the reprogramming
of epigenetic marks that occurs during the first
It should also be determined whether SIRT6
loss causes spontaneous tumour formation in
animals. A study
this year evaluated SIRT6-deficient mice up to 17 months of age and,
surprisingly, found no evidence of tumour for-
mation. Although the number of mice inves-tigated was small, this observation seems to
be at odds with the strong tumorigenic poten-
tial of SIRT6-deficient cells that Sebastián
describe. Studying cancer developmentin larger cohorts of SIRT6-deficient mice is
necessary to resolve this issue.
What molecular mechanisms underlie theobserved metabolic changes in SIRT6-defi-
cient cells? Both the HIF1 and MYC pathwayshave central roles in the metabolic reprogram-ming of cancer cells, and NF-κB signalling andgenomic instability can also promote glycolytic
. Perhaps SIRT6 prevents meta-
bolic rewiring in cancer through several path-ways, which might be redundant or operate in
specific cell types or physiological contexts.
Sebastián and collaborators propose thatinhibition of glycolytic metabolism could be
used to treat tumours that have low SIRT6 lev-
els. Perhaps equally exciting is the prospect that
activation of SIRT6 might be beneficial even in
tumours that arise independently of changes in
20/27 DECEMBER 2012 | VOL 492 | NATURE | 363
NEWS & VIEWSRESEARCH
© 2012 Macmillan Publishers Limited. All rights reserved