Androgen induces 3′UTR shortening of de novo lipogenesis genes by alternative polyadenylation in prostate cancer cells

作者：Weijie Sun, Fei Liang, Hui Zhao, Yun-Mei Wang, Zhongyin Zhou, Hui Xu, Hang Liu, Dong Tang, Anlong Xu, Yonggui Fu, Zhiheng Li, Jun Ouyang, Newton O. Otecko, Benxia Hu, Tengfei Ma, Xin Li, Dong-Dong Wu, Hui Zhao, Ya‐Ping Zhang · 发表于：Science China Life Sciences · 年份：2025 · DOI：10.1007/s11427-024-2740-7 · 被引用次数：4 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、Cancer, Lipids, and Metabolism

Abstract Alternative polyadenylation (APA) is a pervasive mechanism that is emerging as a formidable player in post-transcriptional regulation. The transcriptional landscape can be altered via APA in response to various stimulating factors. Using the PacBio single-molecule long-read sequencing method, we present for the first time the 3′UTR landscape and reveal a global increase of APA events in prostate cancer (PCa) LNCaP cells in response to androgen dihydrotestosterone (DHT), a critical regulator of PCa progression. With evidence from differential gene expression analyses of Illumina RNA-sequencing data, we demonstrated that genes with DHT-induced changes in both expression and APA were enriched in lipid metabolism. These genes predominantly supported de novo fatty acid synthesis, such as FASN and ACSL3 . Furthermore, we showed that an isoform switch to the proximal poly(A) site of these genes depended on the androgen receptor, and the expression of cancer-associated genes was upregulated by the escape of miRNA-regulated repression machinery. To address the role of key gene shortening in PCa, we prepared 22RV1-FS cells missing the distal poly(A) signal of FASN in the AR + PCa cell line 22RV1 using CRISPR/Cas9 technology. As expected, the edited 22RV1-FS cells overexpressed FASN mRNA and protein and were inclined to cell proliferation in vitro and tumorigenesis in vivo . Interestingly, we found that FASN transcripts with a shortened 3′UTR were significantly increased in adv...