| Literature DB >> 29073105 |
Derrick Sek Tong Ong1,2,3, Baoli Hu1,4,5, Yan Wing Ho1, Charles-Etienne Gabriel Sauvé1, Christopher A Bristow6, Qianghu Wang7,8, Asha S Multani9, Peiwen Chen1, Luigi Nezi8, Shan Jiang6, Claire Elizabeth Gorman1, Marta Moreno Monasterio1, Dimpy Koul10, Matteo Marchesini11, Simona Colla11, Eun-Jung Jin12, Erik P Sulman13, Denise J Spring1, Wai-Kwan Alfred Yung10, Roel G W Verhaak14, Lynda Chin8, Y Alan Wang15, Ronald A DePinho15.
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). Published under the PNAS license.Entities:
Keywords: DNA translesion synthesis; glioma stem cells; self-renewal
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Year: 2017 PMID： 29073105 PMCID： PMC5664518 DOI： 10.1073/pnas.1708122114
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205