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PRMT5-mediated FUBP1 methylation accelerates prostate cancer progression
Weiwei Yan, … , Lichen Yin, Zhenfei Li
Weiwei Yan, … , Lichen Yin, Zhenfei Li
Published August 15, 2024
Citation Information: J Clin Invest. 2024;134(18):e175023. https://doi.org/10.1172/JCI175023.
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Research Article Oncology

PRMT5-mediated FUBP1 methylation accelerates prostate cancer progression

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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.

Authors

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

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Figure 6

Involvement of BRD4 in PRMT5-mediated FUBP1 methylation.

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Involvement of BRD4 in PRMT5-mediated FUBP1 methylation.
(A) Effect of d...
(A) Effect of different small molecules on FUBP1 methylation in LNCaP cells. Cells were treated with a variety of small molecules related to transcriptional or metabolic regulation. (B) FUBP1 methylation after treatment with the BRD4 inhibitor I-BET151 in LNCaP cells. (C) Effect of 1 μM I-BET151 on gene expression in LNCaP cells. (D) Enrichment of BRD4 on different gene promoters after I-BET151 treatment. (E and F) Effect of BRD4 on FUBP1 methylation and its function in LNCaP cells. (G) BRD4 enrichment on different gene promoters in LNCaP cells. (H and I) Involvement of PRMT5 in BRD4-regulated FUBP1 methylation. LNCaP cells were treated with I-BET151 with or without PRMT5 siRNA or a PRMT5 inhibitor. (J) The effect of PRMT5 on cell proliferation after I-BET151 treatment. *P < 0.05, **P < 0.01; 1-way ANOVA with Dunnett’s (T3) or Tukey’s multiple-comparison test.

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