AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase

Yohei Yoshihama, Kyle A. LaBella, Eiru Kim, Lori Bertolet, Medina Colic, Jiexi Li, Xiaoying Shang, Chang Jiun Wu, Denise J. Spring, Y. Alan Wang, Traver Hart, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere2026324118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number36
DOIs
StatePublished - Sep 7 2021

Keywords

  • AR
  • JMJD1C demethylase
  • Prostate cancer
  • Synthetic lethality

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core

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