27-羟基胆固醇（27-HC）是一种胆固醇代谢物，也是首个被发现的内源性选择性雌激素受体调节剂（SERM），已被证明在乳腺癌中具有增殖和转移活性。然而，27-HC代谢产物是否调节乳腺癌中的表观遗传标志物及其进展仍不清楚。本研究报告了27-HC抑制常染色质组蛋白赖氨酸甲基转移酶G9a的表达，进一步降低了一组基因上H3K9的二甲基化水平。我们还观察到ERα在G9a启动子上的占位减少，表明27-HC负调控了ERα在G9a启动子上的占位，并发挥了转录抑制作用。此外，通过H3K9me2标记的ChIP-测序研究表明，27-HC处理降低了与癌症进展、增殖和转移相关的一组基因上的H3K9me2标记。我们观察到在27-HC处理后这些基因的上调，进一步确认了这些基因的甲基化丧失。乳腺癌患者组织的免疫组化分析显示，G9a表达与27-HC降解的关键酶CYP7B1呈正相关。总的来说，本研究报告了27-HC通过ERα抑制G9a表达，降低一组基因上H3K9me2的水平，包括在乳腺肿瘤发生和侵袭中起作用的基因，进一步增加其在乳腺癌细胞中的表达。© 2023 The Authors. Journal of Cellular and Molecular Medicine由Cellular and Molecular Medicine基金会和John Wiley & Sons Ltd.出版。

27-hydroxycholesterol (27-HC) is a cholesterol metabolite and the first discovered endogenous selective estrogen receptor modulator (SERM) that has been shown to have proliferative and metastatic activity in breast cancer. However, whether 27-HC metabolite modulates the epigenetic signatures in breast cancer and its progression remains unclear. The current study, reports that 27-HC represses the expression of euchromatic histone lysine methyltransferase G9a, further reducing di-methylation at H3K9 in a subset of genes. We also observed reduced occupancy of ERα at the G9a promoter, indicating that 27-HC negatively regulates the ERα occupancy on the G9a promoter and functions as a transcriptional repressor. Further, ChIP-sequencing for the H3K9me2 mark has demonstrated that 27-HC treatment reduces the H3K9me2 mark on subset of genes linked to cancer progression, proliferation, and metastasis. We observed upregulation of these genes following 27-HC treatment which further confirms the loss of methylation at these genes. Immunohistochemical analysis with breast cancer patient tissues indicated a positive correlation between G9a expression and CYP7B1, a key enzyme of 27-HC catabolism. Overall, this study reports that 27-HC represses G9a expression via ERα and reduces the levels of H3K9me2 on a subset of genes, including the genes that aid in breast tumorigenesis and invasion further, increasing its expression in the breast cancer cells.© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.