m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1
Androgen receptor splice variant 7 (AR-v7), a constitutively active transcription factor, plays a crucial role in the progression of castration-resistant prostate cancer (CRPC). Here, we found that the cleavage and polyadenylation specificity factor 1 (CPSF1) (the largest subunit of the multi-protei...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253122000579 |
| _version_ | 1818283188109180928 |
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| author | Lei Xia Qing Han Xuehui Duan Yinjie Zhu Jiahua Pan Baijun Dong Weiliang Xia Wei Xue Jianjun Sha |
| author_facet | Lei Xia Qing Han Xuehui Duan Yinjie Zhu Jiahua Pan Baijun Dong Weiliang Xia Wei Xue Jianjun Sha |
| author_sort | Lei Xia |
| collection | DOAJ |
| description | Androgen receptor splice variant 7 (AR-v7), a constitutively active transcription factor, plays a crucial role in the progression of castration-resistant prostate cancer (CRPC). Here, we found that the cleavage and polyadenylation specificity factor 1 (CPSF1) (the largest subunit of the multi-protein cleavage and polyadenylation specificity complex), regulated by the E3 ubiquitin ligases SIAH1, promoted AR-v7 expression. The data from microarray-based analysis and clinical specimen-based analysis showed that SIAH1 expression was decreased in PCa and was negatively correlated with aggressive phenotypes of PCa. SIAH1 repressed PCa cell growth and invasion under castrate conditions. SIAH1 directly interacted with CPSF1 and promoted ubiquitination and degradation of CPSF1. CPSF1 expression was negatively correlated with SIAH1 expression, but positively with PCa progression. CPSF1 overexpression switched the AR splicing pattern and facilitated the generation of the oncogenic isoform (AR-v7) by binding to the AAUAAA polyadenylation signal contained in AR-cryptic exon CE3. Functionally, SIAH1 acted as a tumor suppressor in PCa pathogenesis by repressing CPSF1-mediated AR-v7 generation. Finally, we demonstrated that m6A methylation was concerned with the repression of SIAH1 in PCa. Our results define SIAH1/CPSF1/AR-v7 axis as a regulatory factor of PCa progression, providing a promising target for treating PCa. |
| first_indexed | 2024-12-13T00:32:56Z |
| format | Article |
| id | doaj.art-2953ca1c159b4ad49b7ab5096a5d4487 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-13T00:32:56Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-2953ca1c159b4ad49b7ab5096a5d44872022-12-22T00:05:16ZengElsevierMolecular Therapy: Nucleic Acids2162-25312022-06-0128219230m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1Lei Xia0Qing Han1Xuehui Duan2Yinjie Zhu3Jiahua Pan4Baijun Dong5Weiliang Xia6Wei Xue7Jianjun Sha8Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaSchool of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaDepartment of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaDepartment of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaDepartment of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaDepartment of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaSchool of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of ChinaDepartment of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of China; Corresponding author. Wei Xue, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shandong Middle road, Shanghai 200001, China.Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, People’s Republic of China; Corresponding author. Jianjun Sha, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shandong Middle road, Shanghai 200001, China.Androgen receptor splice variant 7 (AR-v7), a constitutively active transcription factor, plays a crucial role in the progression of castration-resistant prostate cancer (CRPC). Here, we found that the cleavage and polyadenylation specificity factor 1 (CPSF1) (the largest subunit of the multi-protein cleavage and polyadenylation specificity complex), regulated by the E3 ubiquitin ligases SIAH1, promoted AR-v7 expression. The data from microarray-based analysis and clinical specimen-based analysis showed that SIAH1 expression was decreased in PCa and was negatively correlated with aggressive phenotypes of PCa. SIAH1 repressed PCa cell growth and invasion under castrate conditions. SIAH1 directly interacted with CPSF1 and promoted ubiquitination and degradation of CPSF1. CPSF1 expression was negatively correlated with SIAH1 expression, but positively with PCa progression. CPSF1 overexpression switched the AR splicing pattern and facilitated the generation of the oncogenic isoform (AR-v7) by binding to the AAUAAA polyadenylation signal contained in AR-cryptic exon CE3. Functionally, SIAH1 acted as a tumor suppressor in PCa pathogenesis by repressing CPSF1-mediated AR-v7 generation. Finally, we demonstrated that m6A methylation was concerned with the repression of SIAH1 in PCa. Our results define SIAH1/CPSF1/AR-v7 axis as a regulatory factor of PCa progression, providing a promising target for treating PCa.http://www.sciencedirect.com/science/article/pii/S2162253122000579MT: RNA/DNA EditingSIAH1CPSF1androgen receptorARAR-v7 |
| spellingShingle | Lei Xia Qing Han Xuehui Duan Yinjie Zhu Jiahua Pan Baijun Dong Weiliang Xia Wei Xue Jianjun Sha m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1 Molecular Therapy: Nucleic Acids MT: RNA/DNA Editing SIAH1 CPSF1 androgen receptor AR AR-v7 |
| title | m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1 |
| title_full | m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1 |
| title_fullStr | m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1 |
| title_full_unstemmed | m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1 |
| title_short | m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1 |
| title_sort | m6a induced repression of siah1 facilitates alternative splicing of androgen receptor variant 7 by regulating cpsf1 |
| topic | MT: RNA/DNA Editing SIAH1 CPSF1 androgen receptor AR AR-v7 |
| url | http://www.sciencedirect.com/science/article/pii/S2162253122000579 |
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