A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer
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 STU...
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| Language: | English |
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06115-z |
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| author | Xiannan Meng Qingxuan Wu Chengsong Cao Wendong Yang Sufang Chu Hongjun Guo Suhua Qi Jin Bai |
| author_facet | Xiannan Meng Qingxuan Wu Chengsong Cao Wendong Yang Sufang Chu Hongjun Guo Suhua Qi Jin Bai |
| author_sort | Xiannan Meng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d56767b3cec54ea3b645315f1b791f1b |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-d56767b3cec54ea3b645315f1b791f1b2025-01-26T12:50:12ZengBMCJournal of Translational Medicine1479-58762025-01-0123112110.1186/s12967-025-06115-zA novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancerXiannan Meng0Qingxuan Wu1Chengsong Cao2Wendong Yang3Sufang Chu4Hongjun Guo5Suhua Qi6Jin Bai7Cancer Institute, Xuzhou Medical UniversitySchool of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical UniversityDepartment of Oncology, Xuzhou Central HospitalCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityDepartment of General Surgery, Xi’an Central HospitalSchool of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityAbstract 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.https://doi.org/10.1186/s12967-025-06115-zCircular RNAs (circRNA)Castration-resistant prostate cancer (CRPC)AR-V7Enzalutamide (ENZ) |
| spellingShingle | Xiannan Meng Qingxuan Wu Chengsong Cao Wendong Yang Sufang Chu Hongjun Guo Suhua Qi Jin Bai A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer Journal of Translational Medicine Circular RNAs (circRNA) Castration-resistant prostate cancer (CRPC) AR-V7 Enzalutamide (ENZ) |
| title | A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer |
| title_full | A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer |
| title_fullStr | A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer |
| title_full_unstemmed | A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer |
| title_short | A novel peptide encoded by circSRCAP confers resistance to enzalutamide by inhibiting the ubiquitin-dependent degradation of AR-V7 in castration-resistant prostate cancer |
| title_sort | novel peptide encoded by circsrcap confers resistance to enzalutamide by inhibiting the ubiquitin dependent degradation of ar v7 in castration resistant prostate cancer |
| topic | Circular RNAs (circRNA) Castration-resistant prostate cancer (CRPC) AR-V7 Enzalutamide (ENZ) |
| url | https://doi.org/10.1186/s12967-025-06115-z |
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