학술논문
The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer
Document Type
article
Author
Beth Adamson; Nicholas Brittain; Laura Walker; Ruaridh Duncan; Sara Luzzi; Pasquale Rescigno; Graham Smith; Suzanne McGill; Richard J.S. Burchmore; Elaine Willmore; Ian Hickson; Craig N. Robson; Denisa Bogdan; Juan M. Jimenez-Vacas; Alec Paschalis; Jonathan Welti; Wei Yuan; Stuart R. McCracken; Rakesh Heer; Adam Sharp; Johann S. de Bono; Luke Gaughan
Source
The Journal of Clinical Investigation, Vol 133, Iss 22 (2023)
Subject
Language
English
ISSN
1558-8238
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.