去泛素酶USP9X和E3连接酶WWP1协调IGF2BP2泛素化稳态,驱动TNBC进展和顺铂敏感性。

IF 9.6 1区 生物学 Q1 CELL BIOLOGY
Tian Xia, Jianyi Zhao, Zhengyu Zhang, Weilin Lu, Yuxin Wang, Xinrui Dong, Mingyi Sang, Linjie Ju, Xu Zhang, Jifu Wei, Qiang Ding
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引用次数: 0

摘要

翻译后修饰(PTMs)对许多n6 -甲基腺苷(m6A)调节蛋白的功能影响尚不清楚。我们之前的研究表明,m6A读取器IGF2BP2通过表观遗传调控驱动三阴性乳腺癌(TNBC)的进展。在这里,我们发现IGF2BP2的泛素化稳态是由USP9X(去泛素化酶)和WWP1 (E3连接酶)的相反作用动态调节的。我们进一步发现USP9X是一种顺铂结合蛋白,顺铂治疗后其失活将这种平衡转向wwp1介导的TNBC中IGF2BP2降解。这抑制了igf2bp2介导的m6a修饰的MYC/CDK6 mrna的稳定和翻译,从而抑制了TNBC的进展。值得注意的是,在体内和体外模型中,USP9X抑制剂WP1130联合低剂量顺铂对TNBC均显示出协同治疗效果。总体而言,我们的研究结果表明,USP9X/WWP1轴维持IGF2BP2泛素化稳态,以调节TNBC中m6a依赖性的致癌功能。至关重要的是,顺铂通过USP9X结合破坏了这种平衡,损害了IGF2BP2的m6A识别能力,揭示了一种新的ups介导的针对TNBC治疗的药物反应机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The deubiquitinase USP9X and E3 ligase WWP1 orchestrate IGF2BP2 ubiquitination homeostasis to drive TNBC progression and cisplatin sensitivity.

The functional impact of post-translational modifications (PTMs) on many N6-methyladenosine (m6A) regulatory proteins remains unclear. Our previous study demonstrated that the m6A reader IGF2BP2 drives triple-negative breast cancer (TNBC) progression through epigenetic regulation. Here, we found that IGF2BP2 ubiquitination homeostasis was dynamically regulated by the opposing actions of USP9X (deubiquitinase) and WWP1 (E3 ligase). We further identified USP9X as a cisplatin-binding protein, whose inactivation upon cisplatin treatment shifts this balance toward WWP1-mediated IGF2BP2 degradation in TNBC. This suppressed IGF2BP2-mediated stabilization and translation of m6A-modified MYC/CDK6 mRNAs, thereby inhibiting TNBC progression. Notably, combined USP9X inhibitor WP1130 and low-dose cisplatin showed synergistic therapeutic efficacy against TNBC in both in vivo and in vitro models. Overall, our findings established that the USP9X/WWP1 axis maintained IGF2BP2 ubiquitination homeostasis to regulate m6A-dependent oncogenic functions in TNBC. Crucially, cisplatin uniquely disrupts this balance through USP9X binding, impairing IGF2BP2's m6A recognition capacity and revealing a novel UPS-mediated drug response mechanism specific to TNBC treatment.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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