JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.
Cancer Res
; 81(4): 1087-1100, 2021 02 15.
Article
in En
| MEDLINE
| ID: mdl-33822745
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Androgen
/
Jumonji Domain-Containing Histone Demethylases
/
Prostatic Neoplasms, Castration-Resistant
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
/
Male
Language:
En
Journal:
Cancer Res
Year:
2021
Document type:
Article
Affiliation country: