Disrupting Paraspeckle Stability by Targeting WTX-NONO Phase Separation Enhances Chemotherapy Efficacy in Gastric Cancer.

IF 16.6 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2025-10-20 DOI:10.1158/0008-5472.can-25-1747

Yangwei Xu,Zaisheng Ye,Zhihao Lin,Xuexia Qian,Yanyan Li,Fei Sun,Zetao Chen,Zhangting Zhao,Junping Bai,Meihang Du,Yi-Chuan Li,Xuanqi Li,Lijun Han,Huanhu Zhang,Mien-Chie Hung,Liwei An,Qingling Zhang

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Abstract

Nuclear paraspeckles play critical roles in orchestrating gene transcription to support tumor development and progression. Elucidating regulators of their dynamic compositions and formation could provide potential targets for treating cancer. Here, we discovered that the short isoform of WTX (WTX-S) specifically disrupted paraspeckle stability. WTX-S selectively interacted with and sequestered NONO (also as p54nrb) from paraspeckles. Mechanistically, interaction between WTX-S and NONO induced formation of nuclear bodies via liquid-liquid phase separation (WTX-NBs). The coiled-coil domain 2 (WTX-CCD2) directly interacted with NONO-CCD to compartmentalize paraspeckle proteins and subsequently disrupt paraspeckle stability. Functionally, the paraspeckle disintegration induced by WTX-NBs resulted in enhanced chemotherapy sensitivity and favorable prognosis in gastric cancer (GC). Importantly, the cell-penetrating synthetic peptide WTXAP, based on the WTX-NONO interface, mimicked WTX-NB-mediated paraspeckle disintegration and exhibited potent antitumor activity. Likewise, treatment with KPT-330, an FDA-approved XPO1 inhibitor, significantly increased the extent of WTX-S-mediated paraspeckle disintegration, sensitizing WTXhigh GC to chemotherapy. Collectively, these findings characterized the function and potential clinical significance of WTX-NBs, offering a strategy for sensitizing GC to chemotherapy.

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靶向WTX-NONO相分离破坏旁散斑稳定性提高胃癌化疗疗效。

核副斑在协调基因转录以支持肿瘤的发生和进展中发挥关键作用。阐明其动态组成和形成的调节因子可以为治疗癌症提供潜在的靶点。在这里，我们发现WTX的短异构体（WTX- s）特异性地破坏了副散斑稳定性。WTX-S选择性地与副斑中的NONO（也称为p54nrb）相互作用并隔离。机制上，WTX-S与NONO的相互作用诱导了液-液相分离（WTX-NBs）核体的形成。螺旋结构域2 （WTX-CCD2）直接与NONO-CCD相互作用，使旁散斑蛋白区隔，随后破坏旁散斑的稳定性。从功能上讲，WTX-NBs诱导的副斑崩解提高了胃癌（GC）的化疗敏感性和良好的预后。重要的是，基于WTX-NONO界面的细胞穿透合成肽WTXAP，模拟了wtx - nb介导的副斑崩解，并表现出强大的抗肿瘤活性。同样，KPT-330 （fda批准的XPO1抑制剂）治疗可显著增加wtx - s介导的副斑崩解程度，使WTXhigh GC对化疗敏感。总的来说，这些发现表征了WTX-NBs的功能和潜在的临床意义，为GC对化疗增敏提供了一种策略。

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

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.