Abstract
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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.