PRMT5 is a critical regulator of breast cancer stem cell function via histone methylationand FOXP1 expression.
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- Barts Cancer Institute
- GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA.
- Institute of Molecular and Cell Biology, A-Star, Singapore
- STRUCTURAL GENOMICS CONSORTIUM
- Cardiff University
Breast cancer progression, treatment resistance and relapse are thought to originate from a small population of tumour cells, the breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of novel therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal, and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2, SET1 recruitment, H3K4me3 and gene expression. Our findings are clinically significant as PRMT5 depletion within established tumour xenografts, or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor, substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance, and suggest that small molecule inhibitors of PRMT5 or downstream targets, could be an effective strategy eliminating this cancer-causing population.
|Publication status||Published - 19 Dec 2017|
- PRMT5 , arginine methylation , breast cancer , cancer stem cells , FOXP1 , self-renewal , epigenetics