环状SRCAP编码的一种新型肽通过抑制去势抵抗性前列腺癌中AR-V7的泛素依赖性降解赋予对恩杂鲁胺的抗性。

A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer.

作者信息

Meng Xiannan, Wu Qingxuan, Cao Chengsong, Yang Wendong, Chu Sufang, Guo Hongjun, Qi Suhua, Bai Jin

机构信息

Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.

School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.

出版信息

J Transl Med. 2025 Jan 23;23(1):108. doi: 10.1186/s12967-025-06115-z.

DOI:10.1186/s12967-025-06115-z

PMID:39844192

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11755828/

Abstract

BACKGROUND

The sustained activation of androgen receptor splice variant-7 (AR-V7) is a key factor in the resistance of castration-resistant prostate cancer (CRPC) to second-generation anti-androgens such as enzalutamide (ENZ). The AR/AR-V7 protein is regulated by the E3 ubiquitin ligase STUB1 and a complex involving HSP70, but the precise mechanism remains unclear.

METHODS

High-throughput RNA sequencing was used to identify differentially expressed circular RNAs (circRNAs) in ENZ-resistant and control CRPC cells. The coding potential of circSRCAP was confirmed by polysome profiling and LC-MS. The function of circSRCAP was validated in vitro and in vivo using gain- and loss-of-function assays. Mechanistic insights were obtained through immunoprecipitation analyses.

RESULTS

A novel ENZ-resistant circRNA, circSRCAP, was identified and shown to be upregulated in ENZ-resistant C4-2B (ENZR-C4-2B) cells, correlating with increased AR-V7 protein levels. circSRCAP is generated via splicing by eIF4A3, forming a loop structure and is exported from the nucleus by the RNA helicase DDX39A. Mechanistically, circSRCAP encodes a 75-amino acid peptide (circSRCAP-75aa) that inhibits the ubiquitination of AR/AR-V7's co-chaperone protein HSP70 by disrupting the interaction with the E3 ligase STUB1. This process results in the upregulation of AR-V7 expression and promotes ENZ resistance in CRPC cells. Xenograft tumor models further confirmed the role of circSRCAP in CRPC progression and its potential as a therapeutic target for ENZ-resistant CRPC.

CONCLUSIONS

circSRCAP provides an epigenetic mechanism influencing AR-V7 stability and offers a promising therapeutic target for treating ENZ-resistant CRPC.

摘要

背景

雄激素受体剪接变体7（AR-V7）的持续激活是去势抵抗性前列腺癌（CRPC）对恩杂鲁胺（ENZ）等第二代抗雄激素药物耐药的关键因素。AR/AR-V7蛋白受E3泛素连接酶STUB1和涉及HSP70的复合物调控，但其确切机制尚不清楚。

方法

采用高通量RNA测序来鉴定恩杂鲁胺耐药和对照CRPC细胞中差异表达的环状RNA（circRNA）。通过多核糖体分析和液相色谱-质谱法证实了circSRCAP的编码潜力。使用功能获得和功能缺失试验在体外和体内验证了circSRCAP的功能。通过免疫沉淀分析获得了机制上的见解。

结果

鉴定出一种新的恩杂鲁胺耐药circRNA，即circSRCAP，并显示其在恩杂鲁胺耐药的C4-2B（ENZR-C4-2B）细胞中上调，与AR-V7蛋白水平升高相关。circSRCAP通过eIF4A3剪接产生，形成环状结构，并由RNA解旋酶DDX39A从细胞核输出。机制上，circSRCAP编码一种75个氨基酸的肽（circSRCAP-75aa），该肽通过破坏与E3连接酶STUB1的相互作用来抑制AR/AR-V7的共伴侣蛋白HSP70的泛素化。这一过程导致AR-V7表达上调，并促进CRPC细胞中的恩杂鲁胺耐药。异种移植肿瘤模型进一步证实了circSRCAP在CRPC进展中的作用及其作为恩杂鲁胺耐药CRPC治疗靶点的潜力。