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

ABSTRACT: MEF2 (MEF2A, B, C, D) transcription factors (TFs) regulate many complex biological responses, spanning from differentiation to stress-adaptation. MEF2’s activities are therefore strictly regulated. A family of transcriptional repressors: the class IIa HDACs, which includes HDAC4, 5, 7, 9, is intimately involved in the fine tuning of MEF2 activities. In many cancer types the physiological cycle of turning on and off of MEF2 transcriptional activities is subverted due to mutations or dysregulations. On the basis of loss-of-function experiments, MEF2 factors are classified sometimes as oncogenes and sometimes as tumor suppressors. With this project we aimed to address this apparent paradox. Soft-tissue sarcomas and leiomyosarcomas (LMSs) in particular are tumors characterized by a strong repression of MEF2, which is achieved through an increase in proteasomal-mediated degradation of MEF2 proteins or in the repression exerted by HDAC4 and HDAC9. MEF2 degradation prevails in a cellular model of low-grade tumors (SK-LMS-1 cells), while in a model of high-grade LMSs (SK-UT-1 cells) MEF2 are converted into transcriptional repressors of specific genome loci. In this latter case the knock down of MEF2D and MEF2A causes the de-repression of some MEF2-target genes and, surprisingly, has a tumor suppressive effect. Our results suggest that MEF2 could provide different contributions during tumor progression in relation to the specific cellular microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94416 | GEO | 2017/04/17

SECONDARY ACCESSION(S): PRJNA369623

REPOSITORIES: GEO

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