The MEF2-HDAC axis is a master regulator of different developmental programs and adaptive responses in adults. In this manuscript 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 up-regulated during acini formation, concomitantly to the exit from the proliferative phase. Up-regulation of MEF2-trascription is coupled to a down-regulation of HDAC7, which occurs independently from changes in mRNA levels, proteasome or autophagy mediated degradation. During acini formation the MEF2-HDAC axis contributes to promote cell cycle exit, through the engagement of the CDK inhibitor CDKN1A. Only in proliferating cells HDAC7 can bind the first intron of the CDKN1A gene, a region characterized by epigenetic markers of active promoters/enhancers. In cells transformed by the oncogene HER2 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 reverted the proliferative defect and re-established a normal acini morphogenesis