It is currently unclear how mammary epithelial cells organize in acinar structures and which genetic signals are involved in this process, even though distinct patterns of gene expression are considered the base to orchestrate fine tuned cellular decisions. MEF2 transcription factors are important players driving and controlling morphogenetic and differentiation processes in several districts of the body and their activity is highly and tightly regulated by class IIa HDACs. Despite described their central role during development, MEF2 factors and class IIa HDACs involvement in epithelial morphogenesis is still not characterized. Here, using 3D culture of human mammary MCF-10A acini as a model of study, we investigated the effect of the MEF2-HDAC pathway to elucidate its contribution in the epithelial side and its alteration by HER2, a known oncogene in breast cancer. We showed that MEF2-dependent transcription is up-regulated during acini formation and is coupled to a down-regulation of HDAC7, the most expressed class IIa HDAC in our model, which occurs independently from changes in mRNA levels, proteasome or autophagy mediated degradation. Pertubation of MEF2 activity, using shRNA lentiviral vectors or overexpressing a MEF2 or HDAC7 inducible form, affects cell proliferation controlling the expression of the cyclin-dependent kinase inhibitor 1A (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 overexpressing the HER2 oncogene 3D epithelial morphogenesis is altered, HDAC7 is continuously expressed and MEF2-dependent transcription is repressed. Importantly reactivation of MEF2 transcription in these cells, blocking HER2 activity or enhancing MEF2 function, reverted the proliferative defect and re-established normal acini morphogenesis
