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Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis.

ABSTRACT: Deregulated activity of the c-Myc protooncogene is a frequent molecular event underlying mouse and human hepatocarcinogenesis. Nonetheless, the mechanisms sustaining c-Myc oncogenic activity in liver cancer remain scarcely delineated. Recently, we showed that the mammalian target of rapamycin complex 1 (mTORC1) cascade is induced and necessary for c-Myc dependent liver tumor development and progression. Since the heat shock factor 1 (HSF1) transcription factor is a major positive regulator of mTORC1 in the cell, we investigated the functional interaction between HSF1 and c-Myc using in vitro and in vivo approaches. We found that ablation of HSF1 restrains the growth of c-Myc-derived mouse hepatocellular carcinoma (HCC) cell lines, where it induces downregulation of c-Myc levels. Conversely, silencing of c-Myc gene in human and mouse HCC cells led to downregulation of HSF1 expression. Most importantly, overexpression of a dominant negative form of HSF1 (HSF1dn) in the mouse liver via hydrodynamic gene delivery resulted in the complete inhibition of mouse hepatocarcinogenesis driven by overexpression of c-Myc. Altogether, the present results indicate that a functional HSF1 is necessary for c-Myc-driven hepatocarcinogenesis. Consequently, targeting HSF1 might represent a novel and effective therapeutic strategy for the treatment of HCC subsets with activated c-Myc signaling.

SUBMITTER: Cigliano A

PROVIDER: S-EPMC5710874 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis.

Cigliano Antonio A Pilo Maria G MG Li Lei L Latte Gavinella G Szydlowska Marta M Simile Maria M MM Paliogiannis Panagiotis P Che Li L Pes Giovanni M GM Palmieri Giuseppe G Sini Maria C MC Cossu Antonio A Porcu Alberto A Vidili Gianpaolo G Seddaiu Maria A MA Pascale Rosa M RM Ribback Silvia S Dombrowski Frank F Chen Xin X Calvisi Diego F DF

Oncotarget 20171003 53

Deregulated activity of the c-Myc protooncogene is a frequent molecular event underlying mouse and human hepatocarcinogenesis. Nonetheless, the mechanisms sustaining c-Myc oncogenic activity in liver cancer remain scarcely delineated. Recently, we showed that the mammalian target of rapamycin complex 1 (mTORC1) cascade is induced and necessary for c-Myc dependent liver tumor development and progression. Since the heat shock factor 1 (HSF1) transcription factor is a major positive regulator of mT ...[more]

PMID: 29207593

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Project description:Background & aimsMounting evidence implicates the Hippo downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in hepatocellular carcinoma (HCC). We investigated the functional contribution of YAP and/or TAZ to c-MYC-induced liver tumor development.MethodsThe requirement for YAP and/or TAZ in c-Myc-driven hepatocarcinogenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout (KO) mice. An hepatocyte-specific inducible TTR-CreERT2 KO system was applied to evaluate the role of YAP and TAZ during tumor progression. Expression patterns of YAP, TAZ, c-MYC, and BCL2L12 were analyzed in human HCC samples.ResultsWe found that the Hippo cascade is inactivated in c-Myc-induced mouse HCC. Intriguingly, TAZ mRNA levels and activation status correlated with c-MYC activity in human and mouse HCC, but YAP mRNA levels did not. We demonstrated that TAZ is a direct transcriptional target of c-MYC. In c-Myc induced murine HCCs, ablation of Taz, but not Yap, completely prevented tumor development. Mechanistically, TAZ was required to avoid c-Myc-induced hepatocyte apoptosis during tumor initiation. The anti-apoptotic BCL2L12 gene was identified as a novel target regulated specifically by YAP/TAZ, whose silencing strongly suppressed c-Myc-driven murine hepatocarcinogenesis. In c-Myc murine HCC lesions, conditional knockout of Taz, but not Yap, led to tumor regression, supporting the requirement of TAZ for c-Myc-driven HCC progression.ConclusionsTAZ is a pivotal player at the crossroad between the c-MYC and Hippo pathways in HCC. Targeting TAZ might be beneficial for the treatment of patients with HCC and c-MYC activation.Lay summaryThe identification of novel treatment targets and approaches for patients with hepatocellular carcinoma is crucial to improve survival outcomes. We identified TAZ as a transcriptional target of c-MYC which plays a critical role in c-MYC-dependent hepatocarcinogenesis. TAZ could potentially be targeted for the treatment of patients with c-MYC-driven hepatocellular carcinoma.

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Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis.

Publications

Deregulated c-Myc requires a functional HSF1 for experimental and human hepatocarcinogenesis.

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