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USP3 通过稳定和去泛素化 SMARCA5 促进前列腺癌中的 DNA 损伤反应和化疗耐药性。

USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer.

机构信息

Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.

Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang, Jiangxi, China.

出版信息

Cell Death Dis. 2024 Nov 5;15(11):790. doi: 10.1038/s41419-024-07117-3.

DOI:10.1038/s41419-024-07117-3
PMID:39500888
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11538284/
Abstract

The chromatin-remodeling enzyme SMARCA5 plays a key role in DNA-templated events including transcription, DNA replication, and DNA repair. Loss of function of the SMARCA5 can cause neurodevelopmental disorder and Williams syndrome. However, the molecular mechanism underlying the regulation of SMARCA5 in prostate cancer remains largely elusive. Here, we report that the deubiquitinating enzyme USP3 directly interacts with SMARCA5 and removes K63-linked polyubiquitination of SMARCA5 to maintain its stability, which promotes DNA damage repair and chemotherapy resistance. Depletion of USP3 or SMARCA5 promoted PCa cells sensitive to docetaxel and overexpression of USP3 restored the cells resistance to docetaxel treatment in SMARCA5 silenced cells in vitro and vivo. Clinically, USP3 was significantly up-regulated in prostate cancer tissues and positively associated with SMARCA5 expression. Collectively, our findings uncover a novel molecular mechanism for the USP3-SMARCA5 axis in regulating DSB repair with an important role in chemotherapy response in human prostate cancers, highlighting that targeting USP3-SMARCA5 axis could be a valuable strategy to treat USP3/SMARCA5-overexpressing chemotherapy-resistant patients and improve drug treatment.

摘要

染色质重塑酶 SMARCA5 在包括转录、DNA 复制和 DNA 修复在内的 DNA 模板事件中发挥关键作用。SMARCA5 功能丧失会导致神经发育障碍和威廉姆斯综合征。然而，SMARCA5 在前列腺癌中的调控的分子机制在很大程度上仍未被揭示。在这里，我们报告去泛素化酶 USP3 与 SMARCA5 直接相互作用，并去除 SMARCA5 的 K63 连接多泛素化以维持其稳定性，从而促进 DNA 损伤修复和化疗耐药性。USP3 或 SMARCA5 的耗竭促进了 PCa 细胞对多西他赛的敏感性，而过表达 USP3 在体外和体内沉默 SMARCA5 的细胞中恢复了对多西他赛治疗的耐药性。临床上，USP3 在前列腺癌组织中显著上调，并与 SMARCA5 表达呈正相关。总之，我们的研究结果揭示了 USP3-SMARCA5 轴在调节 DSB 修复中的新分子机制，在人类前列腺癌的化疗反应中起重要作用，强调靶向 USP3-SMARCA5 轴可能是治疗 USP3/SMARCA5 过表达化疗耐药患者和改善药物治疗的有价值策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/57cb87502b26/41419_2024_7117_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/161c12cdc47e/41419_2024_7117_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/0ceca48633f5/41419_2024_7117_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/b9053db9633c/41419_2024_7117_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/b0aa76a054cb/41419_2024_7117_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/c9dbd7a80097/41419_2024_7117_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/57cb87502b26/41419_2024_7117_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/161c12cdc47e/41419_2024_7117_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/0ceca48633f5/41419_2024_7117_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/b9053db9633c/41419_2024_7117_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/b0aa76a054cb/41419_2024_7117_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/c9dbd7a80097/41419_2024_7117_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/11538284/57cb87502b26/41419_2024_7117_Fig6_HTML.jpg

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