The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer

被引：7

作者：

Adamson, Beth ^{[1
]}

Brittain, Nicholas

Walker, Laura ^{[1
]}

Duncan, Ruaridh ^{[1
]}

Luzzi, Sara ^{[2
]}

Rescigno, Pasquale ^{[1
]}

Smith, Graham ^{[3
]}

McGill, Suzanne ^{[4
]}

Burchmore, Richard J. S. ^{[4
]}

Willmore, Elaine ^{[1
]}

Hickson, Ian ^{[1
]}

Robson, Craig N. ^{[1
]}

Bogdan, Denisa ^{[5
]}

Jimenez-Vacas, Juan M. ^{[5
]}

Paschalis, Alec ^{[5
,6
]}

Welti, Jonathan ^{[5
,6
]}

Yuan, Wei ^{[5
,6
]}

McCracken, Stuart R. ^{[1
]}

Heer, Rakesh ^{[1
,7
]}

Sharp, Adam ^{[5
,6
]}

de Bono, Johann S. ^{[5
,6
]}

Gaughan, Luke ^{[1
]}

机构：

[1] Newcastle Univ, Ctr Canc, Paul OGorman Bldg, Newcastle Upon Tyne, England

[2] Newcastle Univ, Biosci Inst, Int Ctr Life, Newcastle Upon Tyne, England

[3] Newcastle Univ, Bioinformat Support Unit, Med Sch, Newcastle Upon Tyne, England

[4] Univ Glasgow, Coll Med Vet & Life Sci, Wolfson Wohl Canc Res Ctr, Glasgow Poly, Glasgow City, Scotland

[5] Inst Canc Res, London, England

[6] Royal Marsden NHS Fdn Trust, London, England

[7] Imperial Coll London, Div Surg, London, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 22期

关键词：

ANDROGEN RECEPTOR GENE; PROTEIN-KINASE; TELOMERE LENGTH; VARIANT; 7; RNA; EXPRESSION; PHOSPHORYLATION; PROGRESSION; ABIRATERONE; DOMAIN;

D O I：

10.1172/JCI169200

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 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. DNA-PKcs blockade is an effective therapeutic option in advanced AR-V-positive patients with PC.

引用

页数：19

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