TY - JOUR
T1 - PAF promotes stemness and radioresistance of glioma stem cells
AU - Ong, Derrick Sek Tong
AU - Hu, Baoli
AU - Ho, Yan Wing
AU - Sauvé, Charles Etienne Gabriel
AU - Bristow, Christopher A.
AU - Wang, Qianghu
AU - Multani, Asha S.
AU - Chen, Peiwen
AU - Nezi, Luigi
AU - Jiang, Shan
AU - Gorman, Claire Elizabeth
AU - Monasterio, Marta Moreno
AU - Koul, Dimpy
AU - Marchesini, Matteo
AU - Colla, Simona
AU - Jin, Eun Jung
AU - Sulman, Erik P.
AU - Spring, Denise J.
AU - Yung, Wai Kwan Alfred
AU - Verhaak, Roel G.W.
AU - Chin, Lynda
AU - Wang, Y. Alan
AU - DePinho, Ronald A.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank L. K. Denzin (Rutgers University) for the PAF antibody (clone Jyld12); C. G. Liu, X. Liu, J. Zhang, and the MD Anderson Sequencing and Noncoding RNA Program for gene expression profiling; the MD Anderson Flow Cytometry and Cellular Imaging Core Facility supported by Grant NCI P30CA16672 for flow cytometers and FACS; and Drs. J. Chen, H. Piwnica-Worms, G. Peng, and R. Woods (MD Anderson Cancer Center) for critical reading and comments. We also appreciate all members of the R.A.D., L.C., and G. F. Draetta laboratories for fruitful suggestions and discussions. This research was supported by NIH Grant R01 CA084628 (to R.A.D.).
PY - 2017/10/24
Y1 - 2017/10/24
N2 - 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).
AB - 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).
KW - DNA translesion synthesis
KW - Glioma stem cells
KW - Self-renewal
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U2 - 10.1073/pnas.1708122114
DO - 10.1073/pnas.1708122114
M3 - Article
C2 - 29073105
AN - SCOPUS:85032200761
SN - 0027-8424
VL - 114
SP - E9085-E9095
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
ER -