Histone Deacetylase 10 Inhibitors Suppress Progression of Endometriosis via Activation of Interferon Regulatory Factor 6 and Dachshund Homolog 1

ABSTRACT Aim To investigate the mechanisms of histone deacetylase (HDAC) 10 inhibitors (HDAC10Is) action in endometriosis and the target molecules of HDAC10Is. Methods We assessed the effects of HDAC10Is, tucidinostat and TH34, on the proliferation and the cell cycle in human endometriotic cyst stromal cells (ECSCs). Target genes of HDAC10 were identified by RNA sequencing. We assessed the expression of dachshund homolog 1 (DACH1) and interferon regulatory factor 6 (IRF6) mRNA in ECSCs and normal endometrial stromal cells. The functions of DACH1 and IRF6 were confirmed by compulsory expression of these genes in ECSCs using lentivirus. Effects of tucidinostat and TH34 on the promoter acetylation of the DACH1 and IRF6 genes in ECSCs were assessed by chromatin immunoprecipitation assays. Results Both HDAC10Is had an inhibitory effect on the proliferation of ECSCs and caused them to enter cell cycle arrest at G0/G1. DACH1 and IRF6 were identified as the target genes of HDAC10. HDAC10Is caused acetylated histones to accumulate in the promoters of the genes encoding DACH1 and IRF6 in ECSCs. Conclusions These findings indicate that HDAC10 is a factor which contributes to endometriosis pathogenesis by inhibiting DACH1 and IRF6 expression, and that HDAC10Is are therefore promising agents for endometriosis treatment.