A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer

Jinghui Liu; Yue Zhao; Daheng He; Katelyn M. Jones; Shan Tang; Derek B. Allison; Yanquan Zhang; Jing Chen; Qiongsi Zhang; Xinyi Wang; Chaohao Li; Chi Wang; Lang Li; Xiaoqi Liu

doi:10.1016/j.xcrm.2023.101015

A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer

Jinghui Liu, Yue Zhao, Daheng He, Katelyn M. Jones, Shan Tang, Derek B. Allison, Yanquan Zhang, Jing Chen, Qiongsi Zhang, Xinyi Wang, Chaohao Li, Chi Wang, Lang Li, Xiaoqi Liu

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

Abstract

Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.

Original language	English
Article number	101015
Journal	Cell Reports Medicine
Volume	4
Issue number	4
DOIs	https://doi.org/10.1016/j.xcrm.2023.101015
State	Published - Apr 18 2023

Bibliographical note

Funding Information:
This work was supported by NIH R01 CA157429 (X.L.), R01 CA196634 (X.L.), R01 CA264652 (X.L.), and R01 CA256893 (X.L.). This study was aided by grant #IRG 19-140-31 from the American Cancer Society (J.L.). This research was also supported by the Biospecimen Procurement & Translational Pathology , Biostatistics and Bioinformatics , and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center ( P30CA177558 ). We acknowledge Dr. Joshi Alumkal (University of Michigan, Ann Arbor, MI, USA) for sharing the RNA-seq database from the patients with ENZA treatment. We thank Heather Russell-Simmons at the Markey Cancer Center Research Communications Office and Eleanor Erikson for proofreading the paper.

Funding Information:
This work was supported by NIH R01 CA157429 (X.L.), R01 CA196634 (X.L.), R01 CA264652 (X.L.), and R01 CA256893 (X.L.). This study was aided by grant #IRG 19-140-31 from the American Cancer Society (J.L.). This research was also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We acknowledge Dr. Joshi Alumkal (University of Michigan, Ann Arbor, MI, USA) for sharing the RNA-seq database from the patients with ENZA treatment. We thank Heather Russell-Simmons at the Markey Cancer Center Research Communications Office and Eleanor Erikson for proofreading the paper. J.L. designed and performed experiments, analyzed the data, and wrote the manuscript. X.L. designed the research and supervised the project. Y. Zhao, D.H. S.T. C.L. C.W. and L.L. performed the analysis of CRISPR screening, RNA-seq, and other bioinformatics. K.M.J. conducted manuscript editing. D.B.A. evaluated and scored the IHC staining. Y. Zhang conducted the amplification of the CRISPR library. J.C. performed the mass spectrometry assay and analyzed the data. K.M.J. Q.Z. and X.W. conducted xenograft tumor harvesting and some data analysis. The authors declare no competing interests.

Publisher Copyright:
© 2023 The Author(s)

Keywords

ATM
CK1α
CRISPR screening
enzalutamide
prostate cancer

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

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

Access to Document

10.1016/j.xcrm.2023.101015

Cite this

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title = "A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer",

abstract = "Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.",

keywords = "ATM, CK1α, CRISPR screening, enzalutamide, prostate cancer",

author = "Jinghui Liu and Yue Zhao and Daheng He and Jones, {Katelyn M.} and Shan Tang and Allison, {Derek B.} and Yanquan Zhang and Jing Chen and Qiongsi Zhang and Xinyi Wang and Chaohao Li and Chi Wang and Lang Li and Xiaoqi Liu",

note = "Funding Information: This work was supported by NIH R01 CA157429 (X.L.), R01 CA196634 (X.L.), R01 CA264652 (X.L.), and R01 CA256893 (X.L.). This study was aided by grant #IRG 19-140-31 from the American Cancer Society (J.L.). This research was also supported by the Biospecimen Procurement & Translational Pathology , Biostatistics and Bioinformatics , and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center ( P30CA177558 ). We acknowledge Dr. Joshi Alumkal (University of Michigan, Ann Arbor, MI, USA) for sharing the RNA-seq database from the patients with ENZA treatment. We thank Heather Russell-Simmons at the Markey Cancer Center Research Communications Office and Eleanor Erikson for proofreading the paper. Funding Information: This work was supported by NIH R01 CA157429 (X.L.), R01 CA196634 (X.L.), R01 CA264652 (X.L.), and R01 CA256893 (X.L.). This study was aided by grant #IRG 19-140-31 from the American Cancer Society (J.L.). This research was also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We acknowledge Dr. Joshi Alumkal (University of Michigan, Ann Arbor, MI, USA) for sharing the RNA-seq database from the patients with ENZA treatment. We thank Heather Russell-Simmons at the Markey Cancer Center Research Communications Office and Eleanor Erikson for proofreading the paper. J.L. designed and performed experiments, analyzed the data, and wrote the manuscript. X.L. designed the research and supervised the project. Y. Zhao, D.H. S.T. C.L. C.W. and L.L. performed the analysis of CRISPR screening, RNA-seq, and other bioinformatics. K.M.J. conducted manuscript editing. D.B.A. evaluated and scored the IHC staining. Y. Zhang conducted the amplification of the CRISPR library. J.C. performed the mass spectrometry assay and analyzed the data. K.M.J. Q.Z. and X.W. conducted xenograft tumor harvesting and some data analysis. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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T1 - A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer

AU - Liu, Jinghui

AU - Zhao, Yue

AU - He, Daheng

AU - Jones, Katelyn M.

AU - Tang, Shan

AU - Allison, Derek B.

AU - Zhang, Yanquan

AU - Chen, Jing

AU - Zhang, Qiongsi

AU - Wang, Xinyi

AU - Li, Chaohao

AU - Wang, Chi

AU - Li, Lang

AU - Liu, Xiaoqi

N1 - Funding Information: This work was supported by NIH R01 CA157429 (X.L.), R01 CA196634 (X.L.), R01 CA264652 (X.L.), and R01 CA256893 (X.L.). This study was aided by grant #IRG 19-140-31 from the American Cancer Society (J.L.). This research was also supported by the Biospecimen Procurement & Translational Pathology , Biostatistics and Bioinformatics , and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center ( P30CA177558 ). We acknowledge Dr. Joshi Alumkal (University of Michigan, Ann Arbor, MI, USA) for sharing the RNA-seq database from the patients with ENZA treatment. We thank Heather Russell-Simmons at the Markey Cancer Center Research Communications Office and Eleanor Erikson for proofreading the paper. Funding Information: This work was supported by NIH R01 CA157429 (X.L.), R01 CA196634 (X.L.), R01 CA264652 (X.L.), and R01 CA256893 (X.L.). This study was aided by grant #IRG 19-140-31 from the American Cancer Society (J.L.). This research was also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We acknowledge Dr. Joshi Alumkal (University of Michigan, Ann Arbor, MI, USA) for sharing the RNA-seq database from the patients with ENZA treatment. We thank Heather Russell-Simmons at the Markey Cancer Center Research Communications Office and Eleanor Erikson for proofreading the paper. J.L. designed and performed experiments, analyzed the data, and wrote the manuscript. X.L. designed the research and supervised the project. Y. Zhao, D.H. S.T. C.L. C.W. and L.L. performed the analysis of CRISPR screening, RNA-seq, and other bioinformatics. K.M.J. conducted manuscript editing. D.B.A. evaluated and scored the IHC staining. Y. Zhang conducted the amplification of the CRISPR library. J.C. performed the mass spectrometry assay and analyzed the data. K.M.J. Q.Z. and X.W. conducted xenograft tumor harvesting and some data analysis. The authors declare no competing interests. Publisher Copyright: © 2023 The Author(s)

PY - 2023/4/18

Y1 - 2023/4/18

N2 - Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.

AB - Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.

KW - ATM

KW - CK1α

KW - CRISPR screening

KW - enzalutamide

KW - prostate cancer

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A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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