Related Experiment Video
Updated: Nov 10, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer
Alec Paschalis1,2, Jonathan Welti1, Antje J Neeb1
1The Institute of Cancer Research, London, United Kingdom.
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.
Insights
This study identifies JMJD6 as a key protein in generating androgen receptor variant 7 (AR-V7), which drives endocrine-resistant prostate cancer. Targeting JMJD6 may offer a new therapeutic strategy for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Endocrine resistance (EnR) is a major challenge in advanced prostate cancer treatment.
- Androgen receptor (AR) splice variants, particularly AR splice variant 7 (AR-V7), are critical mediators of EnR.
- Understanding the mechanisms regulating AR-V7 is crucial for developing new therapies.
Purpose of the Study:
- To identify proteins essential for the generation of AR-V7.
- To investigate the role of JMJD6 in AR-V7 production and prostate cancer progression.
- To explore JMJD6 as a potential therapeutic target in EnR prostate cancer.
Main Methods:
- Utilized triangulation studies to identify key regulatory proteins.
- Performed siRNA screening of spliceosome-related genes.
- Validated findings in clinical prostate cancer samples and cell models.
- Conducted mutagenesis studies to assess JMJD6 activity.
Main Results:
- Identified JMJD6 as a critical regulator of AR-V7.
- Observed increased JMJD6 protein levels with castration resistance, correlating with higher AR-V7 and shorter survival.
- Demonstrated that JMJD6 knockdown reduces prostate cancer cell growth and AR-V7 levels.
- Found that JMJD6 activity is essential for AR-V7 generation and involves a druggable pocket.
Conclusions:
- JMJD6 plays a vital role in the generation of AR-V7 in advanced prostate cancer.
- JMJD6 is associated with castration resistance and poor prognosis.
- JMJD6 represents a promising therapeutic target for endocrine-resistant prostate cancer.
Related Concept Videos
01:28Nitric Oxide Signaling Pathway
01:16Treatment for Pulmonary Arterial Hypertension: Oxygen Therapy for Respiratory Failure
Oxygen therapy is vital in increasing and maintaining blood oxygen levels in PAH patients. As a result, it aids in reducing fatigue,...
01:23Treatment for Pulmonary Arterial Hypertension: Prostacyclin Receptor Agonists
These agonists bind to the IPR receptor situated on the plasma membrane of the pulmonary artery smooth muscle cells. This binding triggers a cascade of reactions known as the GS-AC-cAMP-PKA pathway. This pathway results in the relaxation of smooth muscle...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:24Regulation of Angiogenesis and Blood Supply
01:28Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...