Sumoylated SnoN interacts with HDAC1 and p300/CBP to regulate EMT in mammary organoids

Abstract

Protein post-translational modification by the small ubiquitin-like modifier (SUMO) regulates the stability, subcellular localization, and interactions of protein substrates with consequences on cellular responses including epithelial-mesenchymal transition (EMT). Transforming growth factor beta (TGFβ) is a potent inducer of EMT with implications in cancer invasion and metastasis. The transcriptional coregulator SnoN suppresses TGFβ-induced EMT in a sumoylation-dependent manner, but the underlying mechanisms have remained largely unknown. Here, we find that sumoylation promotes the interaction of SnoN with the epigenetic regulators histone deacetylase 1 (HDAC1) and histone acetylase p300 in epithelial cells. In gain and loss of function studies, HDAC1 suppresses, whereas p300 promotes, TGFβ-induced morphogenetic changes associated with EMT in three-dimensional multicellular structures derived from mammary epithelial cells or carcinomas. These findings suggest that sumoylated SnoN acts via regulation of histone acetylation to modulate EMT in breast cell organoids. Our study may facilitate the discovery of new biomarkers and therapeutics in breast cancer and other epithelial cell-derived cancers.