TY - JOUR
T1 - Ribosomal protein S11 influences glioma response to TOP2 poisons
AU - Awah, Chidiebere U.
AU - Chen, Li
AU - Bansal, Mukesh
AU - Mahajan, Aayushi
AU - Winter, Jan
AU - Lad, Meeki
AU - Warnke, Louisa
AU - Gonzalez-Buendia, Edgar
AU - Park, Cheol
AU - Zhang, Daniel
AU - Feldstein, Eric
AU - Yu, Dou
AU - Zannikou, Markella
AU - Balyasnikova, Irina V.
AU - Martuscello, Regina
AU - Konerman, Silvana
AU - Győrffy, Balázs
AU - Burdett, Kirsten B.
AU - Scholtens, Denise M.
AU - Stupp, Roger
AU - Ahmed, Atique
AU - Hsu, Patrick
AU - Sonabend, Adam M.
N1 - Funding Information:
Acknowledgements This work was funded by 5DP5OD021356-05 (AMS), P50CA221747 SPORE for Translational Approaches to Brain Cancer (AMS), and Developmental funds from The Robert H. Lurie NCI Cancer Center Support Grant #P30CA060553 (AMS), and generous philanthropic support from Dan and Sharon Moceri. We thank Dr. Ichiro Nakano (University of Alabama), Dr. Charles David James (Northwestern University), and Dr. Shi-Yuan Cheng (Northwestern University) for the kind gift of the GBM xenografts. We thank Dr. Peng Zhang (Northwestern University) for technical support with culture of GBM PDX. We thank Synthego, CA, USA, for the gifts of RPS11 sgRNA guides. Immunofluorescence imaging work was performed at the Center for Advanced Microscopy/Nikon Imaging Center and RHLCCC - Flow Cytometry Core, Northwestern University supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. BG was supported by the NVKP 16-1-2016-0037 grant.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/7/2
Y1 - 2020/7/2
N2 - Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We and others had shown that a subset of glioblastomas, the most malignant of all primary brain tumors in adults, is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, and 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 led to resistance to etoposide and doxorubicin and impaired the induction of proapoptotic gene APAF1 following treatment. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from gliomas and multiple other cancers.
AB - Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We and others had shown that a subset of glioblastomas, the most malignant of all primary brain tumors in adults, is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, and 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 led to resistance to etoposide and doxorubicin and impaired the induction of proapoptotic gene APAF1 following treatment. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from gliomas and multiple other cancers.
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U2 - 10.1038/s41388-020-1342-0
DO - 10.1038/s41388-020-1342-0
M3 - Article
C2 - 32528131
AN - SCOPUS:85086318328
SN - 0950-9232
VL - 39
SP - 5068
EP - 5081
JO - Oncogene
JF - Oncogene
IS - 27
ER -
