PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression

Kelly Chiang, Agnieszka E. Zielinska, Abeer M. Shaaban, Maria Pilar Sanchez-Bailon, James Jarrold, Thomas L. Clarke, Jingxian Zhang, Adele Francis, Louise J. Jones, Sally Smith, Olena Barbash, Ernesto Guccione, Gillian Farnie, Matthew J. Smalley, Clare C. Davies

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

Abstract

Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of 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 H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor 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. Chiang et al. show that the arginine methyltransferase PRMT5 contributes to breast cancer stem cell function, in part through histone methylation regulating FOXP1 expression. Targeting of PRMT5 through depletion or inhibition reduces stem cell frequency in vitro and in vivo, implicating PRMT5 as important in breast cancer pathogenesis.

Original languageEnglish
Pages (from-to)3498-3513
Number of pages16
JournalCell Reports
Volume21
Issue number12
DOIs
StatePublished - 19 Dec 2017

Keywords

  • FOXP1
  • H3R2me2s
  • PRMT5
  • arginine methylation
  • breast cancer
  • breast cancer stem cell
  • drug resistance
  • epigenetics
  • histone methylation
  • self-renewal

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