Identification of MYC-dependent transcriptional programs in oncogene-addicted liver tumors

Theresia R. Kress, Paola Pellanda, Luca Pellegrinet, Valerio Bianchi, Paola Nicoli, Mirko Doni, Camilla Recordati, Salvatore Bianchi, Luca Rotta, Thelma Capra, Micol Rava, Alessandro Verrecchia, Enrico Radaelli, Trevor D. Littlewood, Gerard I. Evan, Bruno Amati

Research output: Contribution to journalArticlepeer-review

Abstract

Tumors driven by activation of the transcription factor MYC generally show oncogene addiction. However, the gene expression programs that depend upon sustained MYC activity remain unknown. In this study, we employed a mouse model of liver carcinoma driven by a reversible tet-MYC transgene, combined with chromatin immunoprecipitation and gene expression profiling to identify MYC-dependent regulatory events. As previously reported, MYC-expressing mice exhibited hepatoblastoma- and hepatocellular carcinoma-like tumors, which regressed when MYC expression was suppressed. We further show that cellular transformation, and thus initiation of liver tumorigenesis, were impaired in mice harboring a MYC mutant unable to associate with the corepressor protein MIZ1 (ZBTB17). Notably, switching off the oncogene in advanced carcinomas revealed that MYC was required for the continuous activation and repression of distinct sets of genes, constituting no more than half of all genes deregulated during tumor progression and an even smaller subset of all MYC-bound genes. Altogether, our data provide the first detailed analysis of a MYC-dependent transcriptional program in a fully developed carcinoma and offer a guide to identifying the critical effectors contributing to MYC-driven tumor maintenance.

Original languageEnglish
Pages (from-to)3463-3472
Number of pages10
JournalCancer Research
Volume76
Issue number12
DOIs
Publication statusPublished - Jun 15 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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