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.

Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation

“…The role of the MYC share in directing the induction or repression of MYC target genes emerged as a common denominator among these systems, strengthening the view that transcriptional amplification, when observed, does not occur as a direct effect of MYC but rather as a secondary consequence of cellular activation (Kress et al 2016). Second, we dissected the effects of MYC on the RNAPII life cycle along transcriptional units, identifying loading as the key regulated step.…”

“…This effect was further reinforced when distinguishing primary (MYC-dependent) from secondary (independent) regulatory events in tet-MYC liver tumors (Supplemental Fig. S1B,C; Kress et al 2016). …”

“…Two other data sets were based on tumors arising in MYC-transgenic mice, including Eµ-myc lymphomas (Sabò et al 2014) and tet-MYC liver carcinomas (Kress et al 2016), each confronted with its normal tissue counterpart (Supplemental Table S1). …”

“…A series of papers proposed that, rather than acting as a gene-specific regulator, MYC acts as a general amplifier of transcriptional activity (Lin et al 2012;Nie et al 2012). However, our re-analysis of the available data led us to reconsider this model and to conclude that the primary activity of MYC lies in the up-and down-regulation of selected sets of genes, RNA "amplification"-when occurring-being best explained as a secondary consequence (Sabò et al 2014;Walz et al 2014;Kress et al 2015Kress et al , 2016.At the mechanistic level, how MYC activates and represses transcription remains to be largely addressed. In particular, a unifying view on the role of MYC in the recruitment and progression of RNA polymerase II (RNAPII) within the transcriptional units of regulated genes and the consequent dynamics of transcriptional regulation is still lacking, owing to a series of reasons.…”

De Novo Palmitate Synthesis Supports Oncogenic Signalling and Tumor Growth Through Diverse Mechanisms: Implications for FASN-Targeted Therapeutics

“…Myc is firmly implicated in many aspects of tumor cell biology including metabolism and regulation of growth, proliferation, and survival [24][25][26][27]. Wnt and Myc pathway impairment by FASN inhibition occurred in the context of additional effects that included mislocalization of lipid-modified oncogenic signalling proteins such as NRas, inhibition of Akt/mTor signalling, and extensive gene expression reprogramming.…”