The mechanisms leading to the constitutive activation of NF-κB in cancers and the pathways upstream and downstream of this activation are not fully understood. In this issue of Cancer Cell, Yamagishi et al. demonstrate that Polycomb-mediated silencing of miR-31 is implicated in the aberrant activation of NF-κB signaling in tumors

Ballaré, Cecilia

Di Croce, Luciano

Uribesalgo, Iris

Elsevier - Publisher Connector 

Cancer Cell
PreviewsMdm2 after DNA damage, it begins to
provide a molecular explanation for how
Mdm2 may act either as an oncogene or
a tumor suppressor, depending upon the
particular context (Manfredi, 2010). This
latter notion has important implications
for the prognosis and treatment of tumors
with aberrant Mdm2 expression.
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369–377.Polycomb Regulates NF-kB Signaling
in Cancer through miRNAIris Uribesalgo,1 Cecilia Ballare´,1 and Luciano Di Croce1,2,*
1Centre de Regulacio´ Geno`mica (CRG) and UPF, 08003 Barcelona, Spain
2Institucio´ Catalana de Recerca i Estudis Avanc¸ats (ICREA), 08010 Barcelona, Spain
*Correspondence: luciano.dicroce@crg.es
DOI 10.1016/j.ccr.2011.12.019
The mechanisms leading to the constitutive activation of NF-kB in cancers and the pathways upstream and
downstream of this activation are not fully understood. In this issue of Cancer Cell, Yamagishi et al. demon-
strate that Polycomb-mediated silencing of miR-31 is implicated in the aberrant activation of NF-kB signaling
in tumors.Differential gene expression distinguishes
one cell type from another and enables
cells to build specialized tissues. Once
a cell fate decision is made, the cell must
be able to silence the transcriptional
programs that could potentially lead to
other lineages, because the DNA content
of all cells is the same. Epigenetic factors
play a crucial role in this type of gene
expression regulation. The Polycomb
group of proteins plays a pivotal role in
silencing and in the long-term repression
of genes implicated in cell fate decisions
(Richly et al., 2010). Polycomb proteins
belong either to Polycomb repressive
complex 1 (PRC1) or PRC2. The PRC2
component EZH2 methylates lysine 27 of
histone H3, which attracts the PRC1
complex; the presence of both PRC1 and
PRC2 at promoter regions leads to tran-
scriptional silencing (Richly et al., 2011).
It is now clear that, in addition to epige-
netic complexes, microRNAs (miRNAs)also contribute greatly to posttranscrip-
tional gene regulation.miRNAsareendog-
enous, short (23 nt) RNAs that suppress
gene expression via sequence-specific
interactions with the 30 untranslated
regions of related mRNA targets. miRNAs
affect gene silencing via both translational
inhibition andmRNA degradation. Several
miRNAs have been reported to have
a direct role in oncogenesis, and indeed,
abnormalmiRNA expression is a common
feature of diverse types of cancers, sug-
gesting potential diagnostic or prognostic
biomarker uses.
The NF-kB transcription factor family
regulates the expression of diverse genes
involved in development, cell growth,
immune responses, apoptosis, and
neoplastic transformation. Activation of
NF-kB is a tightly regulated event. In
non-malignant cells, NF-kB is activated
only after appropriate stimulation, after
which it transiently upregulates thetranscription of its target genes. In tumor
cells, different types of molecular alter-
ationsmay result in an impaired regulation
of NF-kB activation and deregulated
expression of target genes due to consti-
tutively active NF-kB. Recent studies
have also demonstrated that miRNAs
modulate NF-kB signaling in both normal
and pathological scenarios (Lu et al.,
2011; Ma et al., 2011).
Adult T cell leukemia/lymphoma (ATL) is
an aggressive neoplasm of mature CD4+
T lymphocytes caused by the human
T cell leukemia/lymphoma virus type 1
(HTLV-1) infection. Aberrant activation of
NF-kB stimulates cell growth and anti-
apoptotic responses in ATL cells and
thus directly participates in ATL patho-
genesis. Recently, correlations between
the epigenetic machinery, NF-kB activa-
tion, and ATL pathology have been sug-
gested (Sasaki et al., 2011). However,
mechanistic insights are lacking. Tax, an21, January 17, 2012 ª2012 Elsevier Inc. 5
Figure 1. Polycomb-Mediated Silencing of miR-31 Activates the NF-kB Pathway
miR-31 negatively regulates the non-canonical NF-kB pathway by targeting the NIK. Polycomb can modulate NF-kB signaling via miR-31 regulation. PRC2 is
recruited by YY1 to a region upstream of the miR-31 locus and epigenetically silences miR-31 expression. In ATL cells, overexpression of PCR2 components
leads to miR-31 repression, NIK upregulation, and constitutive activation of NF-kB signaling.
Cancer Cell
PreviewsHTLV-1 regulatory protein, has also been
reported to activate the NF-kB pathway.
Tax expression is required at the early
stages of cellular transformation, but Tax
is not expressed in the later states. In
this issue of Cancer Cell, Yamagishi
et al. (2012) describe a Tax-independent
mechanism by which NF-kB is aberrantly
activated in ATL cells through a PRC2-
dependent miR-31 epigenetic silencing.
Given the poor understanding of the
molecular basis of ATL development, Ya-
magishi et al. (2012) initially characterized
the genetic and epigenetic background of
the ATL disease. The authors demon-
strated by miRNA expression microarray
analyses that miR-31 is downregulated
in all primary ATL samples; this suggests
that miR-31 loss is a prerequisite for ATL
development. Using computational algo-
rithms and gene expression microarray
analyses of ATL primary samples, the
authors revealed that the NF-kB-inducing
kinase (NIK) is a downstream target of
miR-31. Intriguingly, NIK plays a central
role in activating non-canonical NF-kB
signaling and has been implicated in ATL
pathogenesis (Saitoh et al., 2008).
The Weinberg lab previously demon-
strated that miR-31 plays a suppressive
role in breast cancer metastasis (Va-
lastyan et al., 2009). Although miR-31
can concomitantly repress multiple prom-
etastatic targets in breast tumors, miR-
31’s impact on metastasis was shown to
be mediated through a small cohort of
these targets. Accordingly, Yamagishi
et al. (2012) now provide evidence for
a high specificity of NIK regulation by
miR-31 in ATL. First, NIK knockdown
and miR-31 ectopic expression produced6 Cancer Cell 21, January 17, 2012 ª2012 Elsimilar effects in ATL cells, such as
triggering an apoptotic response and
attenuating cell proliferation. Second,
expression of a miR-31-resistant NIK
mutant into miR-31-expressing ATL cells
impaired their ability to enter apoptosis.
These results emphasize the ability of
miRNAs to exert their effect by modu-
lating a precise and modest number of
downstream targets in several cell types
and broaden the anti-carcinogenic role
of miR-31 in different types of cancers.
Computational analysis identified YY1
binding motifs upstream of the miR-31
region in both human and mouse. As the
YY1 motifs have been previously shown
to be involved in PRC2 recruitment, the
authors propose that YY1 targets PRC2
to the miR-31 locus and thus induces its
epigenetic silencing. This in turn leads to
increased intracellular levels of NIK and
triggers NF-kB activation (Figure 1). Inter-
estingly, high levels of several Polycomb
proteins and YY1 have been reported
together in primary ATL samples (Sasaki
et al., 2011). These results complement
the data from Yamagishi et al. (2012)
and highlight a novel pathway in ATL
that is triggered by an aberrant overex-
pression of PRC2 complex, leading to
an epigenetic-directed activation of the
NF-kB pathway. It is now relevant to
understand how the PRC2 complex is de-
regulated in ATL.
Understanding the regulatory mecha-
nisms involving Polycomb proteins is
highly relevant considering their important
roles in both normal and cancer cells. In
this respect, the Yamagishi study empha-
sizes two interesting mechanistic features
of PRC2: first, its ability to regulate miRNAsevier Inc.expression in human lymphocytes, as
previously showed in Drosophila and in
mouse ES cells (Enderle et al., 2011; Mar-
son et al., 2008); and second, its ability to
be recruited by YY1. Indeed, as Polycomb
response elements have not been identi-
fied in mammals, several studies have
identified a handful of PRC2 recruiters
that could be cell type-specific. It would
be of interest to study if YY1 binding sites
are frequently present in miRNAs that are
silenced by PRC2 and whether this is cell-
specific.
Strikingly, 12.5% of the ATL cases
studied by Yamagishi et al. (2012) had
genomic deletions of the region where
the human gene that encodes miR-31,
hsa-miR-31, is located. Correspondingly,
several ATL cases with no genetic dele-
tion at hsa-miR-31 presented a severe
downregulation of miR-31 expression.
Thus, this study also opens the possibility
to monitor the expression of miR-31 as
clinical biomarkers for ATL. Furthermore,
the miRNA expression signature in ATL
cells presented in this study revealed 59
other miRNAs to be downregulated,
some of which have known tumor-
suppressive functions. These might also
be relevant for ATL pathogenesis and
warrant further investigation.
The findings by Yamagishi et al. (2012)
further our understanding of the highly
complex transformation phenotype and
oncogenic synergism in ATL. Recent
data highlighted the relevance of NF-kB
activation in Notch1-induced T cell acute
lymphoblastic leukemia and its potential
as a therapeutic target (Espinosa et al.,
2010). The crosstalk between NF-kB and
Polycomb-mediated silencing of miRNAs
Cancer Cell
Previewsdescribed here opens new therapeutic
possibilities for ATL treatment. Targeting
Polycomb activity, restoring the tumor
suppressor miR-31, or inhibiting NIK are
all attractive potential strategies for elimi-
nating ATL tumor cells. Furthermore, the
described involvement of miR-31 in
breast cancer cells (Valastyan et al.,
2009) raises the question of whether
miR-31 silencing through PRC2 occurs
in other type of tumors and whether these
pathways could be also be targets for
molecular therapies in those malignan-
cies. Finally, from a basic biology view-
point, the novel mechanism described
by Yamagishi et al. (2012) might have
a wider role in normal cells, given the
ubiquitous roles of NF-kB, Polycomb,
and miRNAs in several tissues.REFERENCES
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Lu, Z., Li, Y., Takwi, A., Li, B., Zhang, J., Conklin,
D.J., Young, K.H., Martin, R., and Li, Y. (2011).
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Y. (2011). J. Mol. Cell. Biol. 3, 159–166.
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G.M., Brambrink, T., Johnstone, S., Guenther,
M.G., Johnston, W.K., Wernig, M., Newman, J.,
et al. (2008). Cell 134, 521–533.
Richly, H., Rocha-Viegas, L., Ribeiro, J.D.,
Demajo, S., Gundem, G., Lopez-Bigas, N., Naka-Cancer Cellgawa, T., Rospert, S., Ito, T., and Di Croce, L.
(2010). Nature 468, 1124–1128.
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Yamagishi, M., Nakano, K., Miyake, A., Yamochi,
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(2012). Cancer Cell 21, this issue, 121–135.How to Fool a Wonder Drug: Truncate and DimerizeMiriam Molina-Arcas1 and Julian Downward1,*
1Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
*Correspondence: julian.downward@cancer.org.uk
DOI 10.1016/j.ccr.2011.12.017
In a recent paper, Poulikakos et al. describe a new and potentially commonmechanismwhereby melanomas
develop resistance to the BRAF inhibitor vemurafenib by expressing truncated forms of BRAF(V600E) that
can dimerize in the absence of activated RAS. Will it be possible to block this with improved BRAF inhibitor
design?Metastatic melanoma has long been
renowned for being extremely difficult to
treat effectively. However, the last few
years have witnessed dramatic changes
to the landscape of this disease. In 2002,
it was discovered that over 50% of mela-
nomas harbor activating mutations, most
commonly V600E, in the gene encoding
the protein kinase BRAF, which lead to
constitutive activation of the RAF/MEK/
ERK pro-proliferative signaling pathway
(Davies et al., 2002). Within a few years,
the first selective BRAF inhibitor was in
clinical trials producing highly encour-
aging results. In a phase I clinical trial,
the BRAF(V600E) selective inhibitor ve-
murafenib (PLX4032) resulted in complete
or partial regression in the majority of
melanoma patients harboring the
BRAF(V600E) mutation (Flaherty et al.,2010). However, the excitement from
this spectacular result was soon tem-
pered as resistance to the therapy quickly
developed, resulting in response dura-
tions of only 2 to 18 months.
Vemurafenib is only effective in BRAF
mutant cells. In normal tissues and in cells
where the RAF/MEK/ERK pathway is acti-
vated by mutation of the upstream RAS
signaling proteins, vemurafenib actually
enhances signaling. Key to understanding
this surprising result is the fact that RAF
isoforms BRAF and CRAF normally
homo- or heterodimerize following activa-
tion of RAS proteins. RAF inhibitor binding
appears to cause a conformational
change that promotes the formation of
BRAF-CRAF or CRAF-CRAF dimers in
which the drug-inactivated molecule is
able to induce activation of its drug-freepartner within the dimer. On the other
hand, in cells harboring BRAF(V600E),
the levels of activated RAS (GTP bound)
are insufficient to induce dimer formation,
so BRAF(V600E) signals only as a mono-
mer and the inhibitor can completely
block its kinase activity (Hatzivassiliou
et al., 2010; Heidorn et al., 2010; Poulika-
kos et al., 2010) (Figure 1).
This model suggests that molecular
lesions that enhance RAF dimerization in
tumor cells will increase RAF activity
upon drug treatment and promote tumor
resistance. Poulikakos et al. 2011 have
now found evidence for the operation of
just such a mechanism in vemurafenib-
resistant, BRAF(V600E) mutant mela-
noma cell lines, and patient samples.
The authors generated resistant cell lines
by exposing a BRAF(V600E) melanoma21, January 17, 2012 ª2012 Elsevier Inc. 7


Polycomb Regulates NF-κB Signaling in Cancer through miRNA 

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Polycomb Regulates NF-κB Signaling in Cancer through miRNA

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