MEF2 is a converging hub for HDAC4 and PI3K/Akt-induced transformation.

The MEF2-class IIa HDACs axis operates in several differentiation pathways and in numerous adaptive responses. Here we show that nuclear active HDAC4 and HDAC7 display transforming capability. HDAC4 oncogenic potential depends on the repression of a limited set of genes, most of which are MEF2-targets. Genes verified as targets of the MEF2-HDAC axis are also under the influence of the PI3K/Akt pathway that affects MEF2s protein stability. A signature of MEF2-target genes identified by this study is recurrently repressed in soft tissue sarcomas. Correlation studies depicted two distinct groups of STSs: one in which MEF2 repression correlates with PTEN down-regulation and a second group, in which MEF2 repression correlates with HDAC4 levels. Finally, simultaneous pharmacological inhibition of the PI3K/Akt pathway and of the MEF2-HDACs interaction shows additive effects on transcription of MEF2-target genes and on sarcoma cells proliferation. Overall our work pinpoints an important role of the MEF2-HDAC class IIa axis in tumorigenesis.