HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal

• DOI: 10.1038/s41598-018-26319-2
• Publication Date: 2018-05-25T11:41:12Z
• Authors: Lucia Rossi; Cecilia Battistelli; Valeria de Turris; Valeria Noce; Clemens Zwergel; Sergio Valente; Alessandra Moioli; Andrea Manzione; Marco Palladino; Veronica Bordoni; Alessandro Domenici; Paolo Menè; Antonello Mai; Marco Tripodi; Raffaele Strippoli
• Keywords: Trichostatin A; HDAC1; Myofibroblast

Abstract Peritoneal fibrosis is a pathological alteration of the peritoneal membrane occurring in variety conditions including dialysis (PD), post-surgery adhesions and metastases. The acquisition invasive pro-fibrotic abilities by mesothelial cells (MCs) through induction MMT, cell-specific form EMT, plays main role this process. Aim study was to evaluate possible effects histone deacetylase (HDAC) inhibitors, key components epigenetic machinery, counteracting MMT observed MCs isolated from effluent PD patients. HDAC inhibitors with different class/isoform selectivity have been used for pharmacological inhibition. While effect other limited partial E-cadherin re-expression, MS-275, HDAC1-3 inhibitor, promoted: (i) downregulation mesenchymal markers (MMP2, Col1A1, PAI-1, TGFβ1, TGFβRI) (ii) upregulation epithelial (E-cadherin, Occludin), (iii) reacquisition an epithelial-like morphology (iv) marked reduction cellular invasiveness. Results were confirmed HDAC1 genetic silencing. Mechanistically, MS-275 causes: increase nuclear H3 acetylation rescue profile on promoter, Snail functional impairment. Overall, our study, pinpointing HDAC1, revealed new player regulation fibrosis, providing rationale future therapeutic opportunities.