Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms

Ming Zhang; Can Chen; Zequn Lu; Yimin Cai; Yanmin Li; Fuwei Zhang; Yizhuo Liu; Shuoni Chen; Heng Zhang; Shuhui Yang; Hui Gen; Yuan Jiang; Caibo Ning; Jinyu Huang; Wenzhuo Wang; Linyun Fan; Yi Zhang; Meng Jin; Jinxin Han; Zhen Xiong; Ming Cai; Jiuyang Liu; Chaoqun Huang; Xiaojun Yang; Bin Xu; Heng Li; Bin Li; Xu Zhu; Yongchang Wei; Ying Zhu; Jianbo Tian; Xiaoping Miao

doi:10.1053/j.gastro.2023.07.019

Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms

Gastroenterology. 2023 Nov;165(5):1151-1167. doi: 10.1053/j.gastro.2023.07.019. Epub 2023 Aug 3.

Authors

Ming Zhang¹, Can Chen¹, Zequn Lu¹, Yimin Cai², Yanmin Li², Fuwei Zhang², Yizhuo Liu², Shuoni Chen², Heng Zhang², Shuhui Yang², Hui Gen², Yuan Jiang², Caibo Ning², Jinyu Huang², Wenzhuo Wang², Linyun Fan², Yi Zhang³, Meng Jin⁴, Jinxin Han⁵, Zhen Xiong⁵, Ming Cai⁵, Jiuyang Liu⁶, Chaoqun Huang⁶, Xiaojun Yang⁶, Bin Xu⁷, Heng Li⁸, Bin Li², Xu Zhu⁹, Yongchang Wei¹⁰, Ying Zhu², Jianbo Tian¹¹, Xiaoping Miao¹²

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University; Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China; Department of Radiation Oncology, Renmin Hospital of Wuhan University, Wuhan, China.
² Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University; Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
³ Department of Hygiene Toxicology, School of Public Health, Zunyi Medical University, Zunyi, Guizhou, China.
⁴ Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁵ Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
⁷ Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
⁸ Department of Urology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁹ Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
¹⁰ Department of Gastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
¹¹ Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University; Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China; Department of Radiation Oncology, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address: tianjb@whu.edu.cn.
¹² Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University; Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China; Department of Radiation Oncology, Renmin Hospital of Wuhan University, Wuhan, China; Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. Electronic address: xpmiao@whu.edu.cn.

PMID: 37541527
DOI: 10.1053/j.gastro.2023.07.019

Abstract

Background & aims: Dysregulation of alternative splicing is implicated in many human diseases, and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms.

Methods: We performed a comprehensive sQTL analysis to identify genetic variants that control messenger RNA splicing across 33 cancer types from The Cancer Genome Atlas and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multi-ethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes.

Results: The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. In addition, functionally informed polygenic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese (odds ratio, 1.20; 95% CI, 1.12-1.29; P = 8.82 × 10^-7) and European (odds ratio, 1.11; 95% CI, 1.07-1.16; P = 1.13 × 10^-7) populations. rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RNA-binding protein PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells.

Conclusions: Our study provides an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk and serving as biomarkers and therapeutic targets.

Keywords: Alternative Splicing; Arginine Methylation; Functional PRS; PRMT7; sQTLs.