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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PRMT5-mediated FUBP1 methylation accelerates prostate cancer progression

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 2

PRMT5-mediated FUBP1 methylation.

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PRMT5-mediated FUBP1 methylation. (A) FUBP1 methylation status after PRM...
(A) FUBP1 methylation status after PRMT5 or PRMT9 knockdown in HEK293T cells. Scr, scrambled control siRNA. (B) Re-expression of PRMT5 rescues FUBP1 methylation in HEK293T cells. DM1, a PRMT5 enzyme-dead mutant with G365A/R368A mutations; DM2, a PRMT5 enzyme-dead mutant with an E444Q mutation. (C) Status of FUBP1 methylation in different cell lines after treatment with the PRMT5 inhibitor GSK591, 100 nM. (D) PRMT5 inhibition specifically affects FUBP1 methylation at R359/R361/R363 in LNCaP cells. FUBP1 and FUBP13K, a mutant with R359/R361/R363K mutations, were transiently expressed in LNCaP cells. (E) FUBP1 methylation in PRMT5-depleted prostate cancer cell lines. (F) Expression levels of FUBP1 target genes in LNCaP and VCaP cells with PRMT5 depletion. (G) FUBP1 methylation in MTAP-depleted prostate cancer cells. (H) Expression levels of FUBP1 target genes in MTAP-depleted LNCaP and VCaP cells. (I) Endogenous interaction of FUBP1 with PRMT5 in various cell lines. (J) Direct binding of PRMT5 to FUBP1 in vitro. His-FUBP1 was purified from E. coli, and FLAG-PRMT5 was enriched from HEK293T cell lysate. (K) In vitro methylation of FUBP1 by PRMT5. (L) Endogenous FUBP1 methylation and PRMT5 in different cell lines. Results are shown as mean ± SD. **P < 0.01; 1-way ANOVA with Dunnett’s (T3) multiple-comparison test.