The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer.
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Authors
Adamson, B
Brittain, N
Walker, L
Duncan, R
Luzzi, S
Rescigno, P
Smith, G
McGill, S
Burchmore, RJ
Willmore, E
Hickson, I
Robson, CN
Bogdan, D
Jimenez-Vacas, JM
Paschalis, A
Welti, J
Yuan, W
McCracken, SR
Heer, R
Sharp, A
de Bono, JS
Gaughan, L
Brittain, N
Walker, L
Duncan, R
Luzzi, S
Rescigno, P
Smith, G
McGill, S
Burchmore, RJ
Willmore, E
Hickson, I
Robson, CN
Bogdan, D
Jimenez-Vacas, JM
Paschalis, A
Welti, J
Yuan, W
McCracken, SR
Heer, R
Sharp, A
de Bono, JS
Gaughan, L
Document Type
Journal Article
Date
2023-11-15
Date Accepted
2023-09-21
Abstract
Aberrant androgen receptor (AR) signaling drives prostate cancer (PC), and it is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signaling and are refractory to the current repertoire of AR-targeting therapies, which together drive disease progression. There is an unmet clinical need, therefore, to develop more durable PC therapies that can attenuate AR-V function. Exploiting the requirement of coregulatory proteins for AR-V function has the capacity to furnish tractable routes for attenuating persistent oncogenic AR signaling in advanced PC. DNA-PKcs regulates AR-FL transcriptional activity and is upregulated in both early and advanced PC. We hypothesized that DNA-PKcs is critical for AR-V function. Using a proximity biotinylation approach, we demonstrated that the DNA-PK holoenzyme is part of the AR-V7 interactome and is a key regulator of AR-V-mediated transcription and cell growth in models of advanced PC. Crucially, we provide evidence that DNA-PKcs controls global splicing and, via RBMX, regulates the maturation of AR-V and AR-FL transcripts. Ultimately, our data indicate that targeting DNA-PKcs attenuates AR-V signaling and provide evidence that DNA-PKcs blockade is an effective therapeutic option in advanced AR-V-positive patients with PC.
Citation
Journal of Clinical Investigation, 2023, 133 (22), pp. e169200 -
Source Title
Journal of Clinical Investigation
Publisher
AMER SOC CLINICAL INVESTIGATION INC
ISSN
0021-9738
eISSN
1558-8238
Collections
Research Team
PrCa Targeted Therapy
Cancer Biomarkers
Translational & Expt Med
Translational Therapeutic
Cancer Biomarkers
Translational & Expt Med
Translational Therapeutic