PRMT5 is a critical regulator of breast cancer stem cell function via histone methylationand FOXP1 expression.

Research output: Contribution to journalArticlepeer-review

Authors

  • Abeer Shaaban
  • James Jarrold
  • Thomas Clarke
  • Jingxiang Zhang
  • Adele Francis
  • Louise J Jones
  • Sally Smith
  • Olena Barbash
  • Ernesto Guccione
  • Gillian Farnie
  • Matthew J Smalley

Colleges, School and Institutes

External organisations

  • 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

Abstract

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.

Details

Original languageEnglish
Pages (from-to)3498-3513
JournalCell Reports
Volume21
Issue number12
Publication statusPublished - 19 Dec 2017

Keywords

  • PRMT5 , arginine methylation , breast cancer , cancer stem cells , FOXP1 , self-renewal , epigenetics