TAZ is indispensable for c-MYC-induced hepatocarcinogenesis

J Hepatol. 2022 Jan;76(1):123-134. doi: 10.1016/j.jhep.2021.08.021. Epub 2021 Aug 28.

Abstract

Background & aims: Mounting 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.

Methods: The 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.

Results: We 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.

Conclusions: TAZ 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 summary: The 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.

Keywords: BCL2L12; Hepatocellular carcinoma; TAZ; YAP; c-MYC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / physiopathology
  • DNA-Binding Proteins / adverse effects
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Gene Regulatory Networks / genetics
  • Liver Neoplasms / genetics
  • Liver Neoplasms / physiopathology
  • Mice
  • Mice, Knockout
  • Statistics, Nonparametric
  • Transcription Factors / adverse effects
  • Transcription Factors / analysis
  • Transcription Factors / genetics*
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / adverse effects*
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / genetics
  • YAP-Signaling Proteins / adverse effects*
  • YAP-Signaling Proteins / genetics

Substances

  • DNA-Binding Proteins
  • MYCBP protein, human
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • YAP-Signaling Proteins