JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.

Abstract

Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.

• Authors: Alec Paschalis, Jonathan Welti, Antje J Neeb, Wei Yuan, Ines Figueiredo, Rita Pereira, Ana Ferreira, Ruth Riisnaes, Daniel Nava Rodrigues, Juan M Jiménez-Vacas, Soojin Kim, Takuma Uo, Patrizio Di Micco, Anthony Tumber, Md Saiful Islam, Marc A Moesser, Martine Abboud, Akane Kawamura, Bora Gurel, Rossitza Christova, Veronica S Gil, Lorenzo Buroni, Mateus Crespo, Susana Miranda, Maryou B Lambros, Suzanne Carreira, Nina Tunariu, Andrea Alimonti, Bissan Al-Lazikani, Christopher J Schofield, Stephen R Plymate, Adam Sharp, Johann S de Bono, , SU2C/PCF International Prostate Cancer Dream Team
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 4 Pg. 1087-1100 (02 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33822745 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• AR protein, human
• Antineoplastic Agents
• Enzyme Inhibitors
• Protein Isoforms
• Receptors, Androgen
• Oxygenases
• JMJD6 protein, human
• Jumonji Domain-Containing Histone Demethylases

Topics

• Alternative Splicing
• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Cohort Studies
• Enzyme Inhibitors (therapeutic use)
• Gene Expression Regulation, Neoplastic
• Humans
• Jumonji Domain-Containing Histone Demethylases (antagonists & inhibitors, genetics, physiology)
• Male
• Molecular Targeted Therapy
• Oxygenases (genetics, physiology)
• Prognosis
• Prostatic Neoplasms, Castration-Resistant (diagnosis, drug therapy, genetics, mortality)
• Protein Isoforms (genetics, metabolism)
• Receptors, Androgen (chemistry, genetics, metabolism)
• Retrospective Studies