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  3. Targeting PRMT1-mediated SRSF1 methylation to suppress oncogenic exon inclusion events and breast tumorigenesis

Targeting PRMT1-mediated SRSF1 methylation to suppress oncogenic exon inclusion events and breast tumorigenesis

  • Cell Rep. 2023 Nov 7;42(11):113385. doi: 10.1016/j.celrep.2023.113385.
Wen-Juan Li 1,  Ying Huang 1,  Yi-An Lin 1,  Bao-Ding Zhang 2,  Mei-Yan Li 1,  Yi-Qin Zou 1,  Guo-Sheng Hu 1,  Yao-Hui He 1,  Jing-Jing Yang 1,  Bing-Lan Xie 3,  Hai-Hua Huang 4,  Xianming Deng 5,  Wen Liu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.
  • 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China.
  • 3 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China.
  • 4 Department of Pathology, The Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, China.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China. Electronic address: xmdeng@xmu.edu.cn.
  • 6 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian, China; Xiang An Biomedicine Laboratory, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China. Electronic address: w2liu@xmu.edu.cn.
PMID: 37938975 DOI: 10.1016/j.celrep.2023.113385
Abstract

PRMT1 plays a vital role in breast tumorigenesis; however, the underlying molecular mechanisms remain incompletely understood. Herein, we show that PRMT1 plays a critical role in RNA alternative splicing, with a preference for exon inclusion. PRMT1 methylome profiling identifies that PRMT1 methylates the splicing factor SRSF1, which is critical for SRSF1 phosphorylation, SRSF1 binding with RNA, and exon inclusion. In breast tumors, PRMT1 overexpression is associated with increased SRSF1 arginine methylation and aberrant exon inclusion, which are critical for breast Cancer cell growth. In addition, we identify a selective PRMT1 Inhibitor, iPRMT1, which potently inhibits PRMT1-mediated SRSF1 methylation, exon inclusion, and breast Cancer cell growth. Combination treatment with iPRMT1 and inhibitors targeting SRSF1 phosphorylation exhibits an additive effect of suppressing breast Cancer cell growth. In conclusion, our study dissects a mechanism underlying PRMT1-mediated RNA alternative splicing. Thus, PRMT1 has great potential as a therapeutic target in breast Cancer treatment.

Keywords

CP: Cancer; CP: Molecular biology; arginine methylation; breast cancer; drug screen; splicing.

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