RIOK1 phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma.

IF 23.5 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2025-06-04 DOI:10.1038/s43018-025-00984-5

Fanzheng Meng, Hairui Li, Yabin Huang, Chunxu Wang, Yufeng Liu, Chunting Zhang, Danlei Chen, Taofei Zeng, Shenyu Zhang, Yunyun Li, Bo Zhang, Chuandong Lang, Jie Xia, Wanxiang Xiong, Shixiang Pan, Xuedan Sun, Rick F Thorne, Yao Liu, Jiabei Wang, Shugeng Zhang, Ruipeng Song, Jizhou Wang, Lianxin Liu

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引用次数: 0

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) dampens their clinical efficacy in hepatocellular carcinoma (HCC). Stress granules formed by phase separation are essential to stress response and can be involved in therapy resistance, but their mechanisms in HCC are unclear. Here our screen shows that the atypical serine/threonine kinase RIOK1 is highly expressed in HCC, linked to poor prognosis, and transcriptionally activated by NRF2 under various stress conditions. RIOK1 undergoes liquid-liquid phase separation by incorporating IGF2BP1 and G3BP1 into stress granules that sequestrate PTEN messenger RNA reducing its translation. This process activates the pentose phosphate pathway, facilitating stress resolution and cytoprotection against TKI. We further show that the small-molecule inhibitor chidamide downregulates RIOK1 and enhances TKI efficacy. RIOK1-positive stress granules are found in donafenib-resistant tumors from patients with HCC. These findings reveal a link between stress granule dynamics, metabolic reprogramming and HCC progression, offering the potential means to improve TKI efficacy.

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RIOK1相分离通过应激颗粒激活肝癌肿瘤生长限制PTEN翻译。

对酪氨酸激酶抑制剂（TKIs）的耐药性抑制了其在肝细胞癌（HCC）中的临床疗效。相分离形成的应激颗粒对应激反应至关重要，并可能参与治疗抵抗，但其在HCC中的机制尚不清楚。在这里，我们的筛选显示，非典型丝氨酸/苏氨酸激酶RIOK1在HCC中高表达，与预后不良有关，并在各种应激条件下被NRF2转录激活。RIOK1通过将IGF2BP1和G3BP1结合到隔离PTEN信使RNA减少其翻译的应激颗粒中进行液-液相分离。这个过程激活戊糖磷酸途径，促进应激解决和对TKI的细胞保护。我们进一步发现，小分子抑制剂chidamide下调RIOK1并增强TKI的疗效。在HCC患者的多那非尼耐药肿瘤中发现riok1阳性应激颗粒。这些发现揭示了应激颗粒动力学、代谢重编程和HCC进展之间的联系，为提高TKI疗效提供了潜在的手段。

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

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.