Department of Gynecology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China.
J Cell Mol Med. 2021 Nov;25(21):9972-9982. doi: 10.1111/jcmm.16835. Epub 2021 Sep 29.
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.
子宫内膜异位症是生育年龄妇女慢性盆腔痛的最主要原因。此外，组蛋白去乙酰化酶 2（HDAC2）已被确定与子宫内膜异位症有关。然而，HDAC2 的具体机制仍有待进一步研究。因此，本研究旨在探讨 HDAC2 调控肝细胞核因子 4α/富含 AT 的相互作用域 1A（HNF4A/ARID1A）轴在子宫内膜异位症中的机制。本研究获得了子宫内膜异位症细胞系 hEM15A 和临床子宫内膜异位症组织，并在 hEM15A 细胞中进行了增益和缺失功能试验。通过免疫组织化学和 Western blot 分析检测 HDAC2、HNF4A 和 ARID1A 的表达。通过细胞计数试剂盒-8 测定细胞活力，通过 Transwell 测定侵袭，通过流式细胞术测定细胞凋亡。通过染色质免疫沉淀检测 HDAC2 在 HNF4A 启动子区域的富集和 HNF4A 在 ARID1A 启动子区域的富集。建立子宫内膜异位症小鼠模型，然后对异位组织进行 Ki-67 表达的免疫组化和凋亡的 TUNEL 染色。子宫内膜异位症组织中 HDAC2 上调，但 HNF4A 和 ARID1A 下调。HDAC2 通过去乙酰化抑制 HNF4A 的表达，HNF4A 被富集到 ARID1A 启动子区域以激活 ARID1A。沉默 HDAC2 或过表达 HNF4A 或 ARID1A 可减少 hEM15A 细胞的活力和侵袭，增加细胞凋亡。沉默 HDAC2 减少了子宫内膜异位症组织的面积和重量，抑制了子宫内膜异位症细胞的增殖，加速了子宫内膜异位症细胞的凋亡。通过 HNF4A/ARID1A 轴沉默 HDAC2 的抑制作用在小鼠模型中得到重现。综上所述，沉默 HDAC2 通过抑制去乙酰化来上调 HNF4A 以激活 ARID1A，从而防止子宫内膜异位症的发生。
