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

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

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish
Article number8492
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

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    Rossi, L., Battistelli, C., De Turris, V., Noce, V., Zwergel, C., Valente, S., Moioli, A., Manzione, A., Palladino, M., Bordoni, V., Domenici, A., Menè, P., Mai, A., Tripodi, M., & Strippoli, R. (2018). HDAC1 inhibition by MS-275 in mesothelial cells limits cellular invasion and promotes MMT reversal. Scientific Reports, 8(1), [8492]. https://doi.org/10.1038/s41598-018-26319-2