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

Abstract

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.

• Authors: Ravindran Vini, Asha Lekshmi, Swathy Ravindran, Jissa Vinoda Thulaseedharan, Kunjuraman Sujathan, Arumugam Rajavelu, Sreeharshan Sreeja
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 27 Issue 18 Pg. 2744-2755 (09 2023) ISSN: 1582-4934 [Electronic] England
• PMID: 37614064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Estrogen Receptor alpha
• 27-hydroxycholesterol
• Hydroxycholesterols
• Receptors, Estrogen

Topics

• Humans
• Female
• Breast Neoplasms (genetics)
• Estrogen Receptor alpha (genetics)
• Hydroxycholesterols (pharmacology)
• Receptors, Estrogen