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

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.

METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial–mesenchymal transition of renal tubular cells in diabetic kidney disease

“…Additionally, the mesothelial cells (MCs) isolated from effluent of peritoneal dialysis (PD) patients were treated with MS-275, a HDAC1-3 inhibitor, and downregulated mesenchymal markers including TGF-β1 to promote EMT reversal. Further genetic silencing experiments confirmed that HDAC1 played a major role in EMT reversal 23 . Combined with these findings, our experiments suggested that TGF-β1 was the important downstream target of HDAC5-regulated EMT in diabetic kidney disease.…”

Peritoneal fibrosis and epigenetic modulation

“…20 Moreover, in MCs isolated from peritoneal effluent of PD patients who underwent EMT in vivo, then in a model of PDF exposure in vitro, HDAC1 was also highly expressed and associated with the decrease of nuclear histone H3 acetylation. 66 Blockade of HDAC1 with MS-275 rescued the acetylation profile on the E-cadherin promoter and downregulated Snail levels, which further prevented MCs and reversed EMT. 66 Io et al administered SAHA, a nonspecific HDAC inhibitor, to verify its effect on the progression of PF in a mouse model established by intraperitoneal injection of CG.…”

“…66 Blockade of HDAC1 with MS-275 rescued the acetylation profile on the E-cadherin promoter and downregulated Snail levels, which further prevented MCs and reversed EMT. 66 Io et al administered SAHA, a nonspecific HDAC inhibitor, to verify its effect on the progression of PF in a mouse model established by intraperitoneal injection of CG. 67 SAHA increased levels of histone acetylation in injured peritoneum and suppressed peritoneal thickening and mediated upregulation of BMP-7 expression.…”

“…60 Recent studies have revealed that Class I and Class II HDACs are also associated with organ fibrosis. 61 –65 At present, there are only three reports focusing on the relationship between HDACs and PF, and the anti-fibrotic effect of HDAC inhibitors, including MS-275 targeting HDAC1 of Class I, 66 Tubastatin A targeting HDAC6 of Class II, 20 and suberoylanilide hydroxamic acid (SAHA) targeting all classes of HDACs, 67 as shown in Table 1.…”

MEF-2 isoforms' (A-D) roles in development and tumorigenesis

“…When fibrosis occurs, there is a mesothelial to mesenchymal transition (MMT) which causes invasion. MS-275 is a specific class-I HDAC inhibitor which inhibits cellular invasion and promotes MMT reversal in peritoneal fibrosis [268]. HDACi are also used in various preclinical models of immunological diseases such as EAE (experimental autoimmune encephalomyelitis), asthma, and rheumatoid arthritis [269, 270].…”