Journal Article

The co-existence of transcriptional activator and transcriptional repressor MEF2 complexes influences tumor aggressiveness

Brenca, Monica, Polano, Maurizio, Picco, Raffaella, Franforte, Elisa, Brancolini, Claudio, Paluvai, Harikrishnareddy, Dei Tos, Angelo Paolo, Maestro, Roberta, Di Giorgio, Eros, Cefalù, Sebastiano, Rossi, Sabrina

2017

Overview

The contribution of MEF2 TFs to the tumorigenic process is still mysterious. Here we clarify that MEF2 can support both pro-oncogenic or tumor suppressive activities depending on the interaction with co-activators or co-repressors partners. Through these interactions MEF2 supervise histone modifications associated with gene activation/repression, such as H3K4 methylation and H3K27 acetylation. Critical switches for the generation of a MEF2 repressive environment are class IIa HDACs. In leiomyosarcomas (LMS), this two-faced trait of MEF2 is relevant for tumor aggressiveness. Class IIa HDACs are overexpressed in 22% of LMS, where high levels of MEF2, HDAC4 and HDAC9 inversely correlate with overall survival. The knock out of HDAC9 suppresses the transformed phenotype of LMS cells, by restoring the transcriptional proficiency of some MEF2-target loci. HDAC9 coordinates also the demethylation of H3K4me3 at the promoters of MEF2-target genes. Moreover, we show that class IIa HDACs do not bind all the regulative elements bound by MEF2. Hence, in a cell MEF2-target genes actively transcribed and strongly repressed can coexist. However, these repressed MEF2-targets are poised in terms of chromatin signature. Overall our results candidate class IIa HDACs and HDAC9 in particular, as druggable targets for a therapeutic intervention in LMS.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetylation / Apoptosis / Biology and Life Sciences / Breast cancer / Carcinogenesis / Carcinogenesis - genetics / Cell cycle / Cell Line, Tumor / Cell Nucleus - genetics / Chromatin / Demethylation / Development and progression / DNA methylation / DNA Methylation - genetics / Epigenetics / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Genomics / Histone Deacetylases - biosynthesis / Histone Deacetylases - genetics / Humans / Leiomyosarcoma / Leiomyosarcoma - genetics / Leiomyosarcoma - pathology / Medicine and Health Sciences / MEF2 Transcription Factors - biosynthesis / MEF2 Transcription Factors - genetics / Myocyte enhancer factor 2 / Oncology / Pathology / Physiological aspects / Promoters / Repressor Proteins - biosynthesis / Repressor Proteins - genetics / Repressors / Research and Analysis Methods / Studies / Transcription / Transcription factors / Transcriptional Activation - genetics