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

Alec Paschalis; Jonathan Welti; Antje 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 I. Abboud; Akane Kawamura; Bora Gürel; Rossitza Christova; Veronica 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

doi:10.1158/0008-5472.can-20-1807

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

Alec Paschalis(Royal Marsden NHS Foundation Trust), Jonathan Welti(Institute of Cancer Research), Antje Neeb(Institute of Cancer Research), Wei Yuan(Institute of Cancer Research), Ines Figueiredo(Institute of Cancer Research), Rita Pereira(Institute of Cancer Research), Ana Ferreira(Institute of Cancer Research), Ruth Riisnaes(Institute of Cancer Research), Daniel Nava Rodrigues(Institute of Cancer Research), Juan M. Jiménez‐Vacas(Instituto Maimónides de Investigación Biomédica de Córdoba), Soojin Kim(University of Washington), Takuma Uo(University of Washington), Patrizio Di Micco(Institute of Cancer Research), Anthony Tumber(University of Oxford), Md. Saiful Islam(University of Oxford), Marc A. Moesser(University of Oxford), Martine I. Abboud(University of Oxford), Akane Kawamura(University of Oxford), Bora Gürel(Institute of Cancer Research), Rossitza Christova(Institute of Cancer Research), Veronica Gil(Institute of Cancer Research), Lorenzo Buroni(Institute of Cancer Research), Mateus Crespo(Institute of Cancer Research), Susana Miranda(Institute of Cancer Research), Maryou B. Lambros(Institute of Cancer Research), Suzanne Carreira(Institute of Cancer Research), Nina Tunariu(Royal Marsden NHS Foundation Trust), Andrea Alimonti(University of Padua), Bissan Al‐Lazikani(Institute of Cancer Research), Christopher J. Schofield(University of Oxford), Stephen R. Plymate(University of Washington), Adam Sharp(Royal Marsden NHS Foundation Trust), Johann S. de Bono(Royal Marsden NHS Foundation Trust)

Cancer Research

February 15, 2021

10.1158/0008-5472.can-20-1807

Cited by 53Open Access

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Abstract

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 &lt; 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.

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