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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Cell Line
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Cell Line, Tumor
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Cell Nucleus / enzymology
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Cell Nucleus / pathology
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Cells, Cultured
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Gene Expression Regulation, Neoplastic
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Histone Deacetylases / analysis
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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MEF2 Transcription Factors / chemistry
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MEF2 Transcription Factors / genetics
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MEF2 Transcription Factors / metabolism*
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Mice
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Mice, Inbred BALB C
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NIH 3T3 Cells
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Phosphatidylinositol 3-Kinase / metabolism*
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Protein Stability
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Proto-Oncogene Proteins c-akt / metabolism*
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Repressor Proteins / analysis
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Sarcoma / genetics
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Sarcoma / metabolism
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Sarcoma / pathology
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Signal Transduction
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Transcriptional Activation
Substances
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MEF2 Transcription Factors
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Repressor Proteins
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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HDAC4 protein, human
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HDAC7 protein, human
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Hdac5 protein, mouse
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Histone Deacetylases