title: Identification of MYC-Dependent Transcriptional Programs in Oncogene-Addicted Liver Tumors.
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. Cancer Res; 76(12); 3463-72. ©2016 AACR.
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy. Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Theresia R
authors.initials: TR
authors.lastname: Kress
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Pellanda
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, United Kingdom.
authors.forename: Luca
authors.initials: L
authors.lastname: Pellegrinet
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Doni
authors.affiliation: Mouse & Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Recordati
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rotta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Thelma
authors.initials: T
authors.lastname: Capra
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy. Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Ravà
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Verrecchia
authors.affiliation: VIB11 Center for the Biology of Disease, KU Leuven Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Enrico
authors.initials: E
authors.lastname: Radaelli
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, United Kingdom.
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Littlewood
authors.affiliation: Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, United Kingdom.
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy. Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy. bruno.amati@iit.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D051379:Mice; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D016271:Proto-Oncogene Proteins c-myc