SENP3诱导的HADHA去苏酰化通过脂肪酸氧化增强肝内胆管癌化疗敏感性

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-05-02 DOI:10.1016/j.canlet.2025.217770

Jijun Shan , Zhiwen Chen , Mo Chen, Zong Wu, Hongxu Zhu, Xin Jin, Yixiu Wang, Yibin Wu, Zhiwen Ding, Zhen Xiang, Longrong Wang, Yiming Zhao, Zhenhai Lin, Lu Wang

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引用次数: 0

摘要

化疗耐药导致肝内胆管癌（ICC）患者预后不良。本研究旨在探讨化疗耐药的机制，并制定化疗增敏策略。通过患者源性类器官（PDOs）药物筛选和脂质组学分析来研究化疗耐药机制。通过多策略分析，我们发现SENP3以SUMO系统依赖的方式增强化疗敏感性。在机制上，化疗耐药增加了METTL3的表达，通过ythdf2依赖的m6A甲基化修饰调节SENP3 mRNA的稳定性。SENP3与HADHA相互作用并催化其在两个赖氨酸残基上的去苏酰化。具体来说，sumo酰化和泛素化在HADHA的相同修饰位点上表现出串扰，影响其蛋白质稳定性，从而调节脂肪酸氧化（FAO）水平。SENP3、HADHA和USP10的物理相互作用为FAO通路异常激活提供了一种新的分子机制。脂质代谢靶向药物可能是一种有前途的治疗策略，使ICC对化疗敏感。

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SENP3 induced HADHA deSUMOylation enhances intrahepatic cholangiocarcinoma chemotherapy sensitivity via fatty acid oxidation

Chemoresistance contributes to poor outcomes in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the mechanisms underlying chemotherapy resistance and to develop strategies that can sensitize the chemotherapy. Patient derived organoids (PDOs) drug screening and Lipidomics profiling were performed to investigate the chemoresistance mechanism. Through multi-strategy analysis, we found that SENP3 enhanced chemotherapy sensitivity in a SUMO system dependent manner. Mechanistically, chemotherapy resistance increased METTL3 expression, which regulated SENP3 mRNA stability through YTHDF2-dependent m6A methylation modifications. SENP3 interacted with HADHA and catalyzed its deSUMOylation at two lysine residues. Specifically, SUMOylation and ubiquitination exhibited crosstalk at the same modification sites on HADHA, influencing its protein stability and, consequently, regulating fatty acid oxidation (FAO) levels. The physical interaction of SENP3, HADHA, and USP10 provides a novel molecular mechanism for the abnormal activation of FAO pathway. The lipid metabolism-targeting drug could be a promising therapeutic strategy for sensitizing ICC to chemotherapy.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.