2. Academic Validation
  3. Androgen induces 3'UTR shortening of de novo lipogenesis genes by alternative polyadenylation in prostate cancer cells

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

  • Sci China Life Sci. 2025 Jul 8. doi: 10.1007/s11427-024-2740-7.
Wei-Jie Sun # 1 2 3 4,  Fei Liang # 4,  Hui Zhao # 5,  Yun-Mei Wang # 1,  Zhong-Yin Zhou 1,  Hui Xu 6,  Hang Liu 1,  Dong Tang 7,  An-Long Xu 8 9,  Yong-Gui Fu 8,  Xi Li 5,  Jun Ouyang 4,  Newton O Otecko 1,  Ben-Xia Hu 1,  Teng-Fei Ma 4,  Xin Li 7,  Dong-Dong Wu 10 11,  Hui Zhao 12 13,  Ya-Ping Zhang 14 15 16 17
Affiliations

Affiliations

  • 1 Key Laboratory of Genetic Evolution & Animal Models and Yunnan Key Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
  • 2 Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650204, China.
  • 3 Bio-X Center for Interdisciplinary Innovation, Yunnan University, Kunming, 650500, China.
  • 4 State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, 650500, China.
  • 5 Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
  • 6 Reforgene Medicine, Guangzhou, 510530, China.
  • 7 Nextomics Biosciences Institute, Wuhan, 430000, China.
  • 8 State Key Laboratory of Biocontrol, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
  • 9 School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 10 Key Laboratory of Genetic Evolution & Animal Models and Yunnan Key Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China. wudongdong@mail.kiz.ac.cn.
  • 11 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China. wudongdong@mail.kiz.ac.cn.
  • 12 Bio-X Center for Interdisciplinary Innovation, Yunnan University, Kunming, 650500, China. zhaohui@ynu.edu.cn.
  • 13 State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, 650500, China. zhaohui@ynu.edu.cn.
  • 14 Key Laboratory of Genetic Evolution & Animal Models and Yunnan Key Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China. zhangyp@mail.kiz.ac.cn.
  • 15 Bio-X Center for Interdisciplinary Innovation, Yunnan University, Kunming, 650500, China. zhangyp@mail.kiz.ac.cn.
  • 16 State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, 650500, China. zhangyp@mail.kiz.ac.cn.
  • 17 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China. zhangyp@mail.kiz.ac.cn.
  • # Contributed equally.
PMID: 40643802 DOI: 10.1007/s11427-024-2740-7
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 advanced PCa and castration-resistant prostate Cancer compared with benign prostate hyperplasia, suggesting a possible association between usage of the proximal poly(A) site and disease progression. Therefore, our study highlights the importance of the APA mechanism in response to DHT stimulation in PCa cells and provides a novel regulatory mechanism through which DHT-induced APA causes altered expression of de novo lipogenesis genes, with a possible association with the progression of PCa.

Keywords

FASN; de novo lipogenesis gene; APAome; alternative polyadenylation; androgen; prostate cancer.

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