Histone deacetylase HDAC2 silencing prevents endometriosis by activating the HNF4A/ARID1A axis

Abstract

Endometriosis is the most major cause of chronic pelvic pain in women of reproductive age. Moreover, the involvement of histone deacetylase 2 (HDAC2) has been identified in endometriosis. However, the specific mechanism of HDAC2 remains to be further elusive. Therefore, this study was designed to explore the mechanism of HDAC2 orchestrating hepatocyte nuclear factor 4α/AT-rich interactive domain 1A (HNF4A/ARID1A) axis in endometriosis. Endometriosis cell line hEM15A and clinical endometriosis tissues were obtained, followed by gain- and loss-of-function assays in hEM15A cells. HDAC2, HNF4A and ARID1A expression was detected by immunohistochemistry and Western blot analysis. Cell viability was determined by Cell Counting Kit-8 Assay, invasion by Transwell assay and apoptosis by flow cytometry. HDAC2 enrichment in HNF4A promoter region and HNF4A enrichment in ARID1A promoter region was detected through chromatin immunoprecipitation. Mouse models of endometriosis were established, followed by immunohistochemistry of Ki-67 expression and TUNEL staining of apoptosis in ectopic tissues. HDAC2 was upregulated but HNF4A and ARID1A were downregulated in endometriosis tissues. HDAC2 inhibited HNF4A expression by deacetylation, and HNF4A was enriched in ARID1A promoter region to activate ARID1A. Silencing HDAC2 or overexpressing HNF4A or ARID1A diminished the viability and invasion and augmented the apoptosis of hEM15A cells. HDAC2 silencing reduced the area and weight of endometriosis tissues, suppressed endometriosis cell proliferation and accelerated endometriosis cell apoptosis. The inhibitory action of silencing HDAC2 via HNF4A/ARID1A axis was reproduced in mouse models. Collectively, HDAC2 silencing might upregulate HNF4A via repression of deacetylation to activate ARID1A, thus preventing the occurrence of endometriosis.