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

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) AR-positive 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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 36 (09 07 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34475205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Receptors, Androgen
• Tumor Necrosis Factor-alpha
• Histone Demethylases
• JMJD1C protein, human
• Jumonji Domain-Containing Histone Demethylases
• Oxidoreductases, N-Demethylating
• MAP4K4 protein, human
• Protein Serine-Threonine Kinases

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor
• Databases, Genetic
• Histone Demethylases (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Jumonji Domain-Containing Histone Demethylases (genetics, metabolism)
• Male
• Oxidoreductases, N-Demethylating (genetics, metabolism)
• Promoter Regions, Genetic (drug effects)
• Prostate (pathology)
• Prostatic Neoplasms (genetics)
• Protein Serine-Threonine Kinases (genetics)
• Receptors, Androgen (genetics, metabolism)
• Signal Transduction (drug effects)
• Transcriptional Activation (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)