title: The MEF2-HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro.
abstract: The myocyte enhancer factor 2 and histone deacetylase (MEF2-HDAC) axis is a master regulator of different developmental programs and adaptive responses in adults. In this paper, we have investigated the contribution of the axis to the regulation of epithelial morphogenesis, using 3D organotypic cultures of MCF10A cells as a model. We have demonstrated that MEF2 transcriptional activity is upregulated during acini formation, which coincides with exit from the proliferative phase. Upregulation of the transcription of MEF2 proteins is coupled to downregulation of HDAC7, which occurs independently from changes in mRNA levels, and proteasome- or autophagy-mediated degradation. During acini formation, the MEF2-HDAC axis contributes to the promotion of cell cycle exit, through the engagement of the CDK inhibitor CDKN1A. Only in proliferating cells can HDAC7 bind to the first intron of the CDKN1A gene, a region characterized by epigenetic markers of active promoters and enhancers. In cells transformed by the oncogene HER2 (ERBB2), acini morphogenesis is altered, MEF2 transcription is repressed and HDAC7 is continuously expressed. Importantly, reactivation of MEF2 transcriptional activity in these cells, through the use of a HER2 inhibitor or by enhancing MEF2 function, corrected the proliferative defect and re-established normal acini morphogenesis.
authors.affiliation: Dipartiment of Medical and Biological Sciences, Università degli Studi di Udine, P.le Kolbe 4, Udine 33100, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Clocchiatti
authors.affiliation: Dipartiment of Medical and Biological Sciences, Università degli Studi di Udine, P.le Kolbe 4, Udine 33100, Italy.
authors.forename: Eros
authors.initials: E
authors.lastname: Di Giorgio
authors.affiliation: Dipartiment of Medical and Biological Sciences, Università degli Studi di Udine, P.le Kolbe 4, Udine 33100, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Viviani
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Streuli
authors.affiliation: Dipartiment of Medical and Biological Sciences, Università degli Studi di Udine, P.le Kolbe 4, Udine 33100, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sgorbissa
authors.affiliation: Dipartiment of Medical and Biological Sciences, Università degli Studi di Udine, P.le Kolbe 4, Udine 33100, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Picco
authors.affiliation: Dipartiment of Medical and Biological Sciences, Università degli Studi di Udine, P.le Kolbe 4, Udine 33100, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cutano
authors.affiliation: Dipartiment of Medical and Biological Sciences, Università degli Studi di Udine, P.le Kolbe 4, Udine 33100, Italy claudio.brancolini@uniud.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brancolini
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D064326:MEF2 Transcription Factors; D006655:Histone Deacetylases
keywords: 3D culture; Apoptosis; Breast cancer; CDKN1A; Cell cycle; ERBB2; H3K27; HDAC4; HDAC5; HDAC7; HER2; Lapatinib; MEF2A; MEF2D; Morphogenesis; p21