Ribosomal protein S11 influences glioma response to TOP2 poisons

Chidiebere U. Awah; Li Chen; Mukesh Bansal; Aayushi Mahajan; Jan Winter; Meeki Lad; Louisa Warnke; Edgar Gonzalez-Buendia; Cheol Park; Daniel Zhang; Eric Feldstein; Dou Yu; Markella Zannikou; Irina V. Balyasnikova; Regina Martuscello; Silvana Konerman; Balázs Győrffy; Kirsten B. Burdett; Denise M. Scholtens; Roger Stupp; Atique Ahmed; Patrick Hsu; Adam M. Sonabend

doi:10.1038/s41388-020-1342-0

Ribosomal protein S11 influences glioma response to TOP2 poisons

Chidiebere U. Awah, Li Chen, Mukesh Bansal, Aayushi Mahajan, Jan Winter, Meeki Lad, Louisa Warnke, Edgar Gonzalez-Buendia, Cheol Park, Daniel Zhang, Eric Feldstein, Dou Yu, Markella Zannikou, Irina V. Balyasnikova, Regina Martuscello, Silvana Konerman, Balázs Győrffy, Kirsten B. Burdett, Denise M. Scholtens, Roger StuppAtique Ahmed, Patrick Hsu, Adam M. Sonabend^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	5068-5081
Number of pages	14
Journal	Oncogene
Volume	39
Issue number	27
DOIs	https://doi.org/10.1038/s41388-020-1342-0
State	Published - Jul 2 2020

Funding

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.

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41388-020-1342-0

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Awah, C. U., Chen, L., Bansal, M., Mahajan, A., Winter, J., Lad, M., Warnke, L., Gonzalez-Buendia, E., Park, C., Zhang, D., Feldstein, E., Yu, D., Zannikou, M., Balyasnikova, I. V., Martuscello, R., Konerman, S., Győrffy, B., Burdett, K. B., Scholtens, D. M., ... Sonabend, A. M. (2020). Ribosomal protein S11 influences glioma response to TOP2 poisons. Oncogene, 39(27), 5068-5081. https://doi.org/10.1038/s41388-020-1342-0

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abstract = "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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Awah, CU, Chen, L, Bansal, M, Mahajan, A, Winter, J, Lad, M, Warnke, L, Gonzalez-Buendia, E, Park, C, Zhang, D, Feldstein, E, Yu, D, Zannikou, M , Balyasnikova, IV, Martuscello, R, Konerman, S, Győrffy, B, Burdett, KB, Scholtens, DM , Stupp, R , Ahmed, A, Hsu, P & Sonabend, AM 2020, 'Ribosomal protein S11 influences glioma response to TOP2 poisons', Oncogene, vol. 39, no. 27, pp. 5068-5081. https://doi.org/10.1038/s41388-020-1342-0

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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.

PY - 2020/7/2

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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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Ribosomal protein S11 influences glioma response to TOP2 poisons

Abstract

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UN SDGs

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