The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer.
The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer.
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DOI：
10.1172/jci169200
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发表时间：
2023-11-15
影响因子：
15.9
通讯作者：
Gaughan, Luke
中科院分区：
文献类型：
--
作者：
Adamson, Beth;Brittain, Nicholas;Walker, Laura;Duncan, Ruaridh;Luzzi, Sara;Rescigno, Pasquale;Smith, Graham;McGill, Suzanne;Burchmore, Richard J. S.;Willmore, Elaine;Hickson, Ian;Robson, Craig N.;Bogdan, Denisa;Jimenez-Vacas, Juan M.;Paschalis, Alec;Welti, Jonathan;Yuan, Wei;McCracken, Stuart R.;Heer, Rakesh;Sharp, Adam;de Bono, Johann S.;Gaughan, Luke
异常雄激素受体（AR）信号驱动前列腺癌（PC），是一个关键的治疗靶点。虽然最初有效，但选择性剪接AR变体（AR- vs）的产生会影响治疗的效果。与全长AR （AR- fl）相比，AR- vs组成性地激活雄激素信号，并且对当前的AR靶向治疗具有难治性，这些治疗共同推动疾病进展。因此，开发更持久的能够减弱AR-V功能的PC疗法是一个尚未满足的临床需求。利用AR- v功能对协同调节蛋白的需求，有能力提供可处理的途径，以减弱晚期PC中持续的致癌AR信号。DNA-PKcs调节AR-FL的转录活性，在早期和晚期PC中均上调。我们假设DNA-PKcs对AR-V功能至关重要。利用近距离生物素化方法，我们证明了DNA-PK全酶是AR-V7相互作用组的一部分，是ar - v介导的转录和高级PC模型细胞生长的关键调节剂。至关重要的是，我们提供了DNA-PKcs控制全局剪接的证据，并通过RBMX调节AR-V和AR-FL转录本的成熟。最终，我们的数据表明靶向DNA-PKcs可减弱AR-V信号，并提供证据表明DNA-PKcs阻断是晚期AR-V阳性PC患者的有效治疗选择。
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.
DOI：
10.1083/jcb.202002129
发表时间：
2021-01-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Tran JR;Paulson DI;Moresco JJ;Adam SA;Yates JR;Goldman RD;Zheng Y
通讯作者：
Zheng Y
DOI：
10.1016/j.mcpro.2021.100064
发表时间：
2021
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Vélot L;Lessard F;Bérubé-Simard FA;Tav C;Neveu B;Teyssier V;Boudaoud I;Dionne U;Lavoie N;Bilodeau S;Pouliot F;Bisson N
通讯作者：
Bisson N