2. Academic Validation
  3. PRMT5 Is a Critical Regulator of Breast Cancer Stem Cell Function via Histone Methylation and FOXP1 Expression

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

  • Cell Rep. 2017 Dec 19;21(12):3498-3513. doi: 10.1016/j.celrep.2017.11.096.
Kelly Chiang 1,  Agnieszka E Zielinska 1,  Abeer M Shaaban 2,  Maria Pilar Sanchez-Bailon 1,  James Jarrold 1,  Thomas L Clarke 1,  Jingxian Zhang 3,  Adele Francis 2,  Louise J Jones 4,  Sally Smith 4,  Olena Barbash 5,  Ernesto Guccione 6,  Gillian Farnie 7,  Matthew J Smalley 8,  Clare C Davies 9
Affiliations

Affiliations

  • 1 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  • 2 Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, and Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2GW, UK.
  • 3 Institute of Molecular and Cell Biology (IMCB), A(∗)STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos Building #3-06, 138673 Singapore, Singapore.
  • 4 Centre for Tumour Biology, Barts Cancer Institute, A Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London EC1M 6BQ, UK.
  • 5 Cancer Epigenetics DPU, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • 6 Institute of Molecular and Cell Biology (IMCB), A(∗)STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos Building #3-06, 138673 Singapore, Singapore; Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7 Structural Genomics Consortium, Botnar Research Centre, NDORMS, University of Oxford, Oxford OX3 7LD, UK.
  • 8 European Cancer Stem Cell Research Institute, Cardiff School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK.
  • 9 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: c.c.davies@bham.ac.uk.
PMID: 29262329 DOI: 10.1016/j.celrep.2017.11.096
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.

Keywords

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

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