title: MEF2 is a converging hub for histone deacetylase 4 and phosphatidylinositol 3-kinase/Akt-induced transformation.
abstract: The MEF2-class IIa histone deacetylase (HDAC) axis operates in several differentiation pathways and in numerous adaptive responses. We show here 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 phosphatidylinositol 3-kinase (PI3K)/Akt pathway that affects MEF2 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 soft tissue sarcomas: one in which MEF2 repression correlates with PTEN downregulation and a second group in which MEF2 repression correlates with HDAC4 levels. Finally, simultaneous pharmacological inhibition of the PI3K/Akt pathway and of MEF2-HDAC interaction shows additive effects on the 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.
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche, Università degli Studi di Udine, Udine, Italy.
authors.forename: Eros
authors.initials: E
authors.lastname: Di Giorgio
authors.forename: Andrea
authors.initials: A
authors.lastname: Clocchiatti
authors.forename: Sara
authors.initials: S
authors.lastname: Piccinin
authors.forename: Andrea
authors.initials: A
authors.lastname: Sgorbissa
authors.forename: Giulia
authors.initials: G
authors.lastname: Viviani
authors.forename: Paolo
authors.initials: P
authors.lastname: Peruzzo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Romeo
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rossi
authors.forename: Angelo Paolo
authors.initials: AP
authors.lastname: Dei Tos
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
authors.forename: Claudio
authors.initials: C
authors.lastname: Brancolini
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D064326:MEF2 Transcription Factors; D012097:Repressor Proteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; C400300:HDAC4 protein, human; C543273:HDAC7 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
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