FOXA1-dependent PUS1 regulates EIF3b stability in a non-enzymatic pathway mediating prostate cancer bone metastasis.

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-08-19 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.100905
Yongxin Wu, Shengmeng Peng, Bisheng Cheng, Haitao Zhong, Meifeng Cen, Jianhan Fu, Tianlong Luo, Zhenghui Guo, Yiming Lai, Hai Huang
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引用次数: 0

Abstract

Bone metastasis is a significant contributor to the poor prognosis in prostate cancer. Recent evidence highlights the pivotal role of pseudouridine synthases in solid tumor progression, yet the specific enzyme driving prostate cancer metastasis remains unidentified. This study uncovers a novel regulatory mechanism of the FOXA1/PUS1/EIF3b signaling axis in prostate cancer bone metastasis. We identified elevated PUS1 expression in prostate cancer tissues, correlating with higher clinical grade and worse prognosis. Knockdown of PUS1 inhibited metastasis independently of its enzymatic activity, with EIF3b acting as a downstream effector, protected from ubiquitin-mediated degradation by PUS1. Overexpression of EIF3b countered the metastasis suppression due to PUS1 knockdown. Additionally, FOXA1 was shown to enhance PUS1 expression by binding to its promoter. Mogroside IV-E, a specific PUS1 inhibitor, demonstrated potent anti-metastatic effects by reducing PUS1 expression. Our findings highlight the FOXA1/PUS1/EIF3b axis as a critical mediator of prostate cancer bone metastasis and suggest that targeting this pathway could be a promising therapeutic strategy.

依赖于 FOXA1 的 PUS1 在介导前列腺癌骨转移的非酶途径中调节 EIF3b 的稳定性。
骨转移是导致前列腺癌预后不良的一个重要因素。最近的证据强调了假尿苷合成酶在实体瘤进展中的关键作用,但驱动前列腺癌转移的特定酶仍未确定。本研究发现了前列腺癌骨转移中 FOXA1/PUS1/EIF3b 信号轴的新型调控机制。我们发现前列腺癌组织中 PUS1 表达升高,与较高的临床分级和较差的预后相关。敲除 PUS1 可抑制转移,不受其酶活性的影响,而 EIF3b 则作为下游效应物,受到 PUS1 的保护,免受泛素介导的降解。EIF3b的过表达抵消了PUS1敲除对转移的抑制作用。此外,研究还发现 FOXA1 可通过与其启动子结合来增强 PUS1 的表达。Mogroside IV-E是一种特异性PUS1抑制剂,它通过降低PUS1的表达而显示出强大的抗转移作用。我们的研究结果突显了FOXA1/PUS1/EIF3b轴是前列腺癌骨转移的关键介质,并表明靶向这一通路可能是一种很有前景的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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