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

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ICR Authors

Paschalis, Alec
 Yuan, Wei
 Figueiredo, Ines
 Pereira, Ana Rita
 Gurel, Bora
 Gil, Veronica
 Miranda, Susana
 Carreira, Suzanne
 Tunariu, Nina
 Al-Lazikani, Bissan
 Sharp, Adam
 De Bono, Johann

Authors

Paschalis, A
Welti, J
Neeb, AJ
Yuan, W
Figueiredo, I
Pereira, R
Ferreira, A
Riisnaes, R
Rodrigues, DN
Jiménez-Vacas, JM
Kim, S
Uo, T
Micco, PD
Tumber, A
Islam, MS
Moesser, MA
Abboud, M
Kawamura, A
Gurel, B
Christova, R
Gil, VS
Buroni, L
Crespo, M
Miranda, S
Lambros, MB
Carreira, S
Tunariu, N
Alimonti, A
Al-Lazikani, B
Schofield, CJ
Plymate, SR
Sharp, A
de Bono, JS
, SU2C/PCF International Prostate Cancer Dream Team,

Document Type

Journal Article

Date

2021-02-15

Date Accepted

2020-12-02

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.

Citation

CANCER RESEARCH, 2021, 81 (4), pp. 1087 - 1100 (14)

DOI

10.1158/0008-5472.CAN-20-1807

URI

https://repository.icr.ac.uk/handle/internal/4494

Rights

https://www.rioxx.net/licenses/all-rights-reserved

Source Title

Publisher

AMER ASSOC CANCER RESEARCH

ISSN

0008-5472

eISSN

1538-7445

Collections

Cancer Therapeutics
Clinical Studies

Research Team

Computational Biology and Chemogenomics
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Computational Biology and Chemogenomics
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group

Notes