title: Class IIa HDACs repressive activities on MEF2-depedent transcription are associated with poor prognosis of ER⁺ breast tumors.
abstract: MEF2s transcription factors and class IIa HDACs compose a fundamental axis for several differentiation pathways. Functional relationships between this axis and cancer are largely unexplored. We have found that class IIa HDACs are heterogeneously expressed and display redundant activities in breast cancer cells. Applying gene set enrichment analysis to compare the expression profile of a list of putative MEF2 target genes, we have discovered a correlation between the down-regulation of the MEF2 signature and the aggressiveness of ER(+) breast tumors. Kaplan-Meier analysis in ER(+) breast tumors evidenced an association between increased class IIa HDACs expression and reduced survival. The important role of the MEF2-HDAC axis in ER(+) breast cancer was confirmed in cultured cells. MCF7 ER(+) cells were susceptible to silencing of class IIa HDACs in terms of both MEF2-dependent transcription and apoptosis. Conversely, in ER(-) MDA-MB-231 cells, the repressive influence of class IIa HDACs was dispensable. Similarly, a class IIa HDAC-specific inhibitor preferentially promoted the up-regulation of several MEF2 target genes and apoptosis in ER(+) cell lines. The prosurvival function of class IIa HDACs could be explained by the repression of NR4A1/Nur77, a proapoptotic MEF2 target. In summary, our studies underscore a contribution of class IIa HDACs to aggressiveness of ER(+) tumors.-Clocchiatti, A., Di Giorgio, E., Ingrao, S., Meyer-Almes, F.-J., Tripodo, C., Brancolini, C. Class IIa HDACs repressive activities on MEF2-depedent transcription are associated with poor prognosis of ER(+) breast tumors.
authors.affiliation: Dipartimento di Scienze Mediche e Biologiche Universita' di Udine. P.le Kolbe 4-33100, Udine, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Clocchiatti
authors.forename: Eros
authors.initials: E
authors.lastname: Di Giorgio
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ingrao
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Meyer-Almes
authors.forename: Claudio
authors.initials: C
authors.lastname: Tripodo
authors.forename: Claudio
authors.initials: C
authors.lastname: Brancolini
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D018006:Myogenic Regulatory Factors; C539821:NR4A1 protein, human; D009363:Neoplasm Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011960:Receptors, Estrogen; D006655:Histone Deacetylases