PRMT5-mediated FUBP1 methylation accelerates prostate cancer progression

Weiwei Yan; Xun Liu; Xuefeng Qiu; Xuebin Zhang; Jiahui Chen; Kai Xiao; Ping Wu; Chao Peng; Xiaolin Hu; Zengming Wang; Jun Qin; Liming Sun; Luonan Chen; Denglong Wu; Shengsong Huang; Lichen Yin; Zhenfei Li

doi:10.1172/JCI175023

PRMT5-mediated FUBP1 methylation accelerates prostate cancer progression

J Clin Invest. 2024 Aug 15;134(18):e175023. doi: 10.1172/JCI175023.

Authors

Weiwei Yan¹, Xun Liu², Xuefeng Qiu³, Xuebin Zhang¹, Jiahui Chen¹, Kai Xiao¹, Ping Wu⁴, Chao Peng⁴, Xiaolin Hu⁵, Zengming Wang⁶, Jun Qin⁶, Liming Sun¹, Luonan Chen¹, Denglong Wu⁷, Shengsong Huang⁷, Lichen Yin², Zhenfei Li^{1

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Affiliations

¹ Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
² Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, China.
³ Department of Urology, Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, China.
⁴ National Facility for Protein Science Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
⁵ State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
⁷ Department of Urology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
⁸ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.

Abstract

Strategies beyond hormone-related therapy need to be developed to improve prostate cancer mortality. Here, we show that FUBP1 and its methylation were essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppressed the development of prostate cancer. FUBP1 accelerated prostate cancer development in various preclinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence in our patient cohort. Suppressed prostate cancer progression was observed in various genetic mouse models expressing the FUBP1 mutant deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in various preclinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potential therapeutic strategy for prostate cancer management.

Keywords: Oncology; Peptides; Prostate cancer; Therapeutics.

MeSH terms

Animals
Cell Line, Tumor
DNA Helicases* / genetics
DNA Helicases* / metabolism
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Disease Progression
Humans
Male
Methylation
Mice
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / pathology
Protein-Arginine N-Methyltransferases* / genetics
Protein-Arginine N-Methyltransferases* / metabolism
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

DNA-Binding Proteins
Protein-Arginine N-Methyltransferases
RNA-Binding Proteins
PRMT5 protein, human
DNA Helicases
FUBP1 protein, human
Prmt5 protein, mouse
Transcription Factors