The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer
Beth Adamson, Nicholas Brittain, Laura Walker, R. Scott Duncan, Sara Luzzi, Pasquale Rescigno, Graham Smith, Suzanne McGill, Richard Burchmore, Elaine Willmore, Ian Hickson, Craig Robson, Denisa Bogdan, Juan M. Jiménez‐Vacas, Alec Paschalis, Jonathan Welti, Wei Yuan, Stuart McCracken, Rakesh Heer, Adam Sharp, Johann S. de Bono, Luke Gaughan
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.