27‐Hydroxycholesterol represses G9a expression via oestrogen receptor alpha in breast cancer

Abstract

Abstract27‐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.