PAF promotes stemness and radioresistance of glioma stem cells

Derrick Sek Tong Ong, Baoli Hu, Yan Wing Ho, Charles Etienne Gabriel Sauvé, Christopher A. Bristow, Qianghu Wang, Asha S. Multani, Peiwen Chen, Luigi Nezi, Shan Jiang, Claire Elizabeth Gorman, Marta Moreno Monasterio, Dimpy Koul, Matteo Marchesini, Simona Colla, Eun Jung Jin, Erik P. Sulman, Denise J. Spring, Wai Kwan Alfred Yung, Roel G.W. VerhaakLynda Chin, Y. Alan Wang, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

An integrated genomic and functional analysis to elucidate DNA damage signaling factors promoting self-renewal of glioma stem cells (GSCs) identified proliferating cell nuclear antigen (PCNA)- associated factor (PAF) up-regulation in glioblastoma. PAF is preferentially overexpressed in GSCs. Its depletion impairs maintenance of self-renewal without promoting differentiation and reduces tumorinitiating cell frequency. Combined transcriptomic and metabolomic analyses revealed that PAF supports GSC maintenance, in part, by influencing DNA replication and pyrimidine metabolism pathways. PAF interacts with PCNA and regulates PCNA-associated DNA translesion synthesis (TLS); consequently, PAF depletion in combination with radiation generated fewer tumorspheres compared with radiation alone. Correspondingly, pharmacological impairment of DNA replication and TLS phenocopied the effect of PAF depletion in compromising GSC self-renewal and radioresistance, providing preclinical proof of principle that combined TLS inhibition and radiation therapy may be a viable therapeutic option in the treatment of glioblastoma multiforme (GBM).

Original languageEnglish (US)
Pages (from-to)E9085-E9095
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number43
DOIs
StatePublished - Oct 24 2017

Keywords

  • DNA translesion synthesis
  • Glioma stem cells
  • Self-renewal

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility

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