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靶向 KDM4A-AS1 抑制 AR/AR-Vs 的去泛素化作用，增强 CRPC 对恩扎卢胺的反应。

Targeting KDM4A-AS1 represses AR/AR-Vs deubiquitination and enhances enzalutamide response in CRPC.

机构信息

Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China.

出版信息

Oncogene. 2022 Jan;41(3):387-399. doi: 10.1038/s41388-021-02103-x. Epub 2021 Nov 10.

DOI:10.1038/s41388-021-02103-x
PMID:34759344
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8755543/
Abstract

Castration-resistant prostate cancer (CRPC) is a highly malignant type of advanced cancer resistant to androgen deprivation therapy. One of the important mechanisms for the development of CRPC is the persistent imbalanced regulation of AR and AR splice variants (AR/AR-Vs). In this study, we reported KDM4A-AS1, a recently discovered lncRNA, as a tumor promoter that was significantly increased in CRPC cell lines and cancer tissues. Depletion of KDM4A-AS1 significantly reduced cell viability, proliferation, migration in vitro, and tumor growth in vivo. We found that by binding to the NTD domain, KDM4A-AS1 enhances the stability of USP14-AR/AR-Vs complex, and promoted AR/AR-Vs deubiquitination to protect it from MDM2-mediated ubiquitin-proteasome degradation. Moreover, KDM4A-AS1 was found to enhance CRPC drug resistance to enzalutamide by repressing AR/AR-Vs degradation; antisense oligonucleotide drugs targeting KDM4A-AS1 significantly reduced the growth of tumors with enzalutamide resistance. Taken together, our results indicated that KDM4A-AS1 played an important role in the progression of CRPC and enzalutamide resistance by regulating AR/AR-Vs deubiquitination; targeting KDM4A-AS1 has broad clinical application potential.

摘要

去势抵抗性前列腺癌（CRPC）是一种高度恶性的晚期癌症，对雄激素剥夺疗法具有抗性。CRPC 发展的一个重要机制是 AR 和 AR 剪接变体（AR/AR-Vs）的持续失衡调节。在这项研究中，我们报告了 KDM4A-AS1，一种新发现的 lncRNA，作为一种肿瘤促进剂，在 CRPC 细胞系和癌症组织中显著增加。KDM4A-AS1 的耗竭显著降低了细胞活力、增殖、体外迁移和体内肿瘤生长。我们发现，通过与 NTD 结构域结合，KDM4A-AS1 增强了 USP14-AR/AR-Vs 复合物的稳定性，并促进了 AR/AR-Vs 的去泛素化，以防止其被 MDM2 介导的泛素蛋白酶体降解。此外，我们发现 KDM4A-AS1 通过抑制 AR/AR-Vs 降解来增强 CRPC 对恩杂鲁胺的耐药性；针对 KDM4A-AS1 的反义寡核苷酸药物显著降低了恩杂鲁胺耐药肿瘤的生长。总之，我们的结果表明，KDM4A-AS1 通过调节 AR/AR-Vs 的去泛素化在 CRPC 和恩杂鲁胺耐药的进展中发挥了重要作用；靶向 KDM4A-AS1 具有广泛的临床应用潜力。

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