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  • [Proc Natl Acad Sci U S A.] PAF promotes stemness and radioresistance of glioma stem cells.

    The University of Texas MD Anderson Cancer Center/ Wang YA*, DePinho RA*

  • 출처
    Proc Natl Acad Sci U S A.
  • 등재일
    2017 Oct 24
  • 저널이슈번호
    114(43):E9086-E9095. doi: 10.1073/pnas.1708122114. Epub 2017 Oct 9.
  • 내용

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    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). 

     

    Author information

    Ong DST1,2,3, Hu B1,4,5, Ho YW1, Sauvé CG1, Bristow CA6, Wang Q7,8, Multani AS9, Chen P1, Nezi L8, Jiang S6, Gorman CE1, Monasterio MM1, Koul D10, Marchesini M11, Colla S11, Jin EJ12, Sulman EP13, Spring DJ1, Yung WA10, Verhaak RGW14, Chin L8, Wang YA15, DePinho RA15.

    1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.2Department of Physiology, National University of Singapore, Singapore 117597, Singapore.3Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore 138673, Singapore.4Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.5Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.6Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.7Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.8Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.9Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.10Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.11Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.12Department of Biological Sciences, Wonkwang University, Iksan, CB, 570-749, Korea.13Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.14The Jackson Laboratory, Farmington, CT 06032.15Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; yalanwang@mdanderson.org rdepinho@mdanderson.org. 

  • 키워드
    DNA translesion synthesis; glioma stem cells; self-renewal
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