4.7 Article

m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1

期刊

MOLECULAR THERAPY-NUCLEIC ACIDS
卷 28, 期 -, 页码 219-230

出版社

CELL PRESS
DOI: 10.1016/j.omtn.2022.03.008

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资金

  1. National Natural Science Foundation of China [81772742, 81702840, 81702542, 81901747]
  2. Science and Technology Commission of Shanghai Municipality [19ZR143100, 19411967400]
  3. Shanghai Shenkang Hospital Development Center [SHDC12015125, 16CR3049A]
  4. Shanghai Municipal Commission of Health and Family Planning [201640247]
  5. Shanghai Jiao Tong University [YG2017MS47, YG2017MS52]

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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.
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.

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