气候变化领域集成服务门户(CCPortal): AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase

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DOI	10.1073/pnas.2026324118
	AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase
	Yoshihama Y.; LaBella K.A.; Kim E.; Bertolet L.; Colic M.; Li J.; Shang X.; Wu C.-J.; Spring D.J.; Wang Y.A.; Hart T.; DePinho R.A.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:36
英文摘要	Prostate cancer is a leading cause of cancer-related mortality in men. The widespread use of androgen receptor (AR) inhibitors has generated an increased incidence of AR-negative prostate cancer, triggering the need for effective therapies for such patients. Here, analysis of public genome-wide CRISPR screens in human prostate cancer cell lines identified histone demethylase JMJD1C (KDM3C) as an AR-negative context-specific vulnerability. Secondary validation studies in multiple cell lines and organoids, including isogenic models, confirmed that small hairpin RNA (shRNA)-mediated depletion of JMJD1C potently inhibited growth specifically in AR-negative prostate cancer cells. To explore the cooperative interactions of AR and JMJD1C, we performed comparative transcriptomics of 1) isogenic AR-positive versus AR-negative prostate cancer cells, 2) ARpositive versus AR-negative prostate cancer tumors, and 3) isogenic JMJD1C-expressing versus JMJD1C-depleted AR-negative prostate cancer cells. Loss of AR or JMJD1C generates a modest tumor necrosis factor alpha (TNFα) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNFα signature in human prostate cancer, suggesting TNFα signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNFα treatment and, conversely, TNFα pathway inhibition via inhibition of its downstream effector MAP4K4 partially reversed the growth defect of JMJD1C-depleted AR-negative prostate cancer cells. Given the deleterious systemic side effects of TNFα therapy in humans and the viability of JMJD1C-knockout mice, the identification of JMJD1C inhibition as a specific vulnerability in AR-negative prostate cancer may provide an alternative drug target for prostate cancer patients progressing on AR inhibitor therapy. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	AR; JMJD1C demethylase; Prostate cancer; Synthetic lethality
语种	英语
scopus关键词	androgen receptor; doxycycline; histone demethylase; JMJD1C demethylase; short hairpin RNA; transcriptome; tumor necrosis factor; unclassified drug; androgen receptor; histone demethylase; JMJD1C protein, human; MAP4K4 protein, human; n demethylase; signal peptide; tumor necrosis factor; androgen receptor negative prostate cancer; antineoplastic activity; Article; cancer screening; clustered regularly interspaced short palindromic repeat; controlled study; drug targeting; enzyme activity; gene deletion; gene expression regulation; genome-wide association study; growth inhibition; organoid; prostate cancer; prostate cancer cell line; protein depletion; protein expression; protein protein interaction; protein targeting; signal transduction; TMF alpha signaling; upregulation; validation process; apoptosis; drug effect; genetic database; genetics; human; male; metabolism; pathology; promoter region; prostate; prostate tumor; transcription initiation; tumor cell line; Apoptosis; Cell Line, Tumor; Databases, Genetic; Histone Demethylases; Humans; Intracellular Signaling Peptides and Proteins; Jumonji Domain-Containing Histone Demethylases; Male; Oxidoreductases, N-Demethylating; Promoter Regions, Genetic; Prostate; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Receptors, Androgen; Signal Transduction; Transcriptional Activation; Tumor Necrosis Factor-alpha
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251025
作者单位	Department of Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, United States; Department of Bioinformatics and Computational Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, United States; Department of Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, United States
推荐引用方式 GB/T 7714	Yoshihama Y.,LaBella K.A.,Kim E.,et al. AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase[J],2021,118(36).
APA	Yoshihama Y..,LaBella K.A..,Kim E..,Bertolet L..,Colic M..,...&DePinho R.A..(2021).AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase.Proceedings of the National Academy of Sciences of the United States of America,118(36).
MLA	Yoshihama Y.,et al."AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase".Proceedings of the National Academy of Sciences of the United States of America 118.36(2021).