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 progres-sion 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 pheno-types of PCa. SIAH1 repressed PCa cell growth and invasion un-der castrate conditions. SIAH1 directly interacted with CPSF1 and promoted ubiquitination and degradation of CPSF1. CPSF1 expression was negatively correlated with SIAH1 expres-sion, but positively with PCa progression. CPSF1 overexpres-sion 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 gen-eration. 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.

Automated summary

This study identifies a mechanism that regulates the expression of a specific protein and gene variant, which is associated with the progression of castration-resistant prostate cancer. This finding may provide a new therapeutic target for treating this disease.