Page 82 - ebook HCC

80 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 81
FEBRUARY 13 - 16, 2014

BETA-CATENIN SIGNALLING AND HCC ONCOGENIC TRANSCRIPTIONAL REGULATORS
METABOLISM
Kai Breuhahn 1
1 Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
Sabine Colnot , Angélique Gougelet , Cyril Torre , Philippe Veber , Chiara Sartor ,
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Cécile Godard , Christine Perret 1 Corresponding author’s e-mail: kai.breuhahn@med.uni-heidelberg.de
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1 Cochin Institute U1016, INSERM, Paris, France
Corresponding author’s e-mail: sabine.colnot@inserm.fr Transcriptional regulators (transcription factors and co-factors) integrate and process input
signals of different (oncogenic) pathways and therefore represent cellular bottlenecks
that regulate tumor cell biology. Genomic and transcriptomic data of primary human liver
Introduction: β-catenin signaling can be both a physiological and an oncogenic pathway cancer revealed that many of these factors were dysregulated in subgroups of HCCs
in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its with a more aggressive phenotype, suggesting that transcriptional regulators collect input
essential metabolic function. It is activated by mutations in 20 to 40% of hepatocellular information in order to promote tumor initiation and progression.
BASIC SPEAKERS ABSTRACTS Aims: β-catenin forms a transcriptional complex together with its nuclear partner Tcf4. overexpression of the transcriptional co-activator yes-associated protein (YAP) leads BASIC SPEAKERS ABSTRACTS
Recent studies demonstrate that dysregulation of the Hippo signaling pathway is critically
carcinomas with specific metabolic features.
involved in hepatocarcinogenesis. Deletion of essential Hippo-pathway constituents or
to the development of liver cancer. However, the underlying molecular mechanisms in
We aimed at identifying at which extent this complex is involved in the genetic metabolic
programme of the zonal liver, and if this has consequences in the pathogenesis of
hepatocarcinogenesis have not been defined so far. Nuclear accumulation of YAP in
β-catenin-mutated HCC in humans.
almost 70% of human HCCs is significantly correlated with tumor cell proliferation and
dedifferentiation. By using cross-species analysis of expression data, the Notch ligand
Methodology: We deciphered the molecular determinants of β-catenin-dependent
zonal transcription using mice with β-catenin-activated or -inactivated hepatocytes,
HCC cells. TEAD4 was identified as the transcription factor required for YAP-dependent
regulation of Jag-1. YAP-induced activation of the Jag-1/Notch pathway significantly
characterizing in vivo their chromatin occupancy by Tcf4 and β-catenin (ChIP-Seq), their Jagged-1 (Jag-1) was identified as a downstream target of YAP in primary hepatocytes and
transcriptome (mRNA-Seq) and their metabolome (nHPLC/ms-ms). correlated with poor prognosis of HCC patients. Transgenic mice with inducible expression
of constitutively active YAP S127A showed hepatomegaly (after 4 weeks) and eventually tumor
Results: We found that Tcf4 DNA-bindings depend on β-catenin. Tcf4/β-catenin binds formation (after 10 weeks). The additional knock-out of Jag-1 reduced hepatomegaly on
Wnt-responsive elements preferentially around β-catenin-induced genes. In contrast, the basis of diminished proliferation; however, tumor formation was not affected.
genes repressed by β-catenin bind Tcf4 on Hnf4-responsive elements. β-catenin, Tcf4 Although transcriptional regulators are believed to be nondruggable owing to large and
and Hnf4α interact, dictating β-catenin transcription which is antagonistic to that elicited stable DNA/protein surface interactions, recent results suggest that disruption of the YAP/
by Hnf4α. Finally, we find the drug/bile metabolism pathway to be the one most heavily TEAD interaction through specific small compounds may provide promising approaches
targeted by β-catenin, partly through xenobiotic nuclear receptors. for the treatment of HCCs with increased YAP levels.
Conclusions: We conclude that β-catenin patterns the zonal liver together with Tcf4,
Hnf4α and xenobiotic nuclear receptors. This network represses lipid metabolism, and
exacerbates glutamine, drug and bile metabolism, mirroring hepatocellular carcinomas
with β-catenin mutational activation.