PAF promotes stemness and radioresistance of glioma stem cells.
Document Type
Article
Publication Date
10-24-2017
JAX Source
Proc Natl Acad Sci U S A 2017 Oct 24; 114(43):E9086-E9095.
Volume
114
Issue
43
First Page
9086
Last Page
9086
ISSN
1091-6490
PMID
29073105
DOI
https://doi.org/10.1073/pnas.1708122114
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 tumor-initiating 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). Proc Natl Acad Sci U S A 2017 Oct 24; 114(43):E9086-E9095.
Recommended Citation
Ong D,
Hu B,
Ho Y,
Sauvé C,
Bristow C,
Wang Q,
Multani A,
Chen P,
Nezi L,
Jiang S,
Gorman C,
Monasterio M,
Koul D,
Marchesini M,
Colla S,
Jin E,
Sulman E,
Spring D,
Yung W,
Verhaak R,
Chin L,
Wang Y,
DePinho R.
PAF promotes stemness and radioresistance of glioma stem cells. Proc Natl Acad Sci U S A 2017 Oct 24; 114(43):E9086-E9095.