RNF5 exacerbates steatotic HCC by enhancing fatty acid oxidation via the improvement of CPT1A stability

IF 9.1 1区 医学 Q1 ONCOLOGY
Xi Chen , Yang-Wen-Qing Zhang , Hui Ren , Caixia Dai , Minghe Zhang , Xiaomian Li , Kequan Xu , Jinghua Li , Yi Ju , Xiaoyu Pan , Peng Xia , Weijie Ma , Wenzhi He , Tiangen Wu , Yufeng Yuan
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Abstract

Non-alcoholic fatty liver disease (NAFLD) is expected to become the leading risk factor for liver cancer, surpassing viral hepatitis. Unlike viral hepatitis-related hepatocellular carcinoma (HCC), the role of excessive nutrient supply in steatotic HCC is not well understood, hindering effective prevention and treatment strategies. Therefore, it is crucial to identify key molecules in the pathogenesis of steatotic HCC, investigate changes in metabolic reprogramming due to excessive fatty acid (FA) supply, understand its molecular mechanisms, and find potential therapeutic targets. Trans-species transcriptome analysis identified Ring Finger Protein 5 (RNF5) as a critical regulator of steatotic HCC. RNF5 upregulation is associated with poor prognosis in steatotic HCC compared to canonical HCC. In vitro and in vivo studies showed that RNF5 exacerbates HCC in the presence of additional FA supply. Lipidomics and transcriptome analyses revealed that RNF5 significantly increases carnitine palmitoyltransferase 1A (CPT1A) mRNA levels and is positively correlated with fatty acid oxidation (FAO). Protein interaction analysis demonstrated that RNF5 promotes K63-type ubiquitination of insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), enhancing CPT1A mRNA stabilization through m6A modification. Additionally, peroxisome proliferator-activated receptor gamma (PPARγ) was found to activate RNF5 expression specifically in HCC cells. Mechanistically, excessive exogenous FAs reorganize FA metabolism in HCC cells, worsening steatotic HCC via the PPARγ-RNF5-IGF2BP1-CPT1A axis. This study highlights a distinct FA metabolism pattern in steatotic HCC, providing valuable insights for potential therapeutic targets.

Abstract Image

RNF5通过改善CPT1A的稳定性来增强脂肪酸氧化,从而加重脂肪变性HCC。
非酒精性脂肪性肝病(NAFLD)有望超过病毒性肝炎成为肝癌的主要危险因素。与病毒性肝炎相关的肝细胞癌(HCC)不同,过度营养供应在脂肪变性HCC中的作用尚不清楚,阻碍了有效的预防和治疗策略。因此,确定脂肪变性HCC发病机制的关键分子,研究脂肪酸过量(FA)供应导致的代谢重编程变化,了解其分子机制,寻找潜在的治疗靶点至关重要。跨物种转录组分析发现环指蛋白5 (RNF5)是脂肪变性HCC的关键调节因子。与典型HCC相比,脂肪变性HCC中RNF5上调与预后不良相关。体外和体内研究表明,在FA供应增加的情况下,RNF5会加重HCC。脂质组学和转录组学分析显示,RNF5显著增加肉毒碱棕榈酰基转移酶1A (CPT1A) mRNA水平,并与脂肪酸氧化(FAO)呈正相关。蛋白相互作用分析表明,RNF5促进胰岛素样生长因子-2 mRNA结合蛋白1 (IGF2BP1)的k63型泛素化,通过m6A修饰增强CPT1A mRNA的稳定性。此外,研究发现过氧化物酶体增殖物激活受体γ (PPARγ)在HCC细胞中特异性激活RNF5表达。在机制上,过量的外源性FAs重组HCC细胞中的FA代谢,通过PPARγ-RNF5-IGF2BP1-CPT1A轴使脂肪变性HCC恶化。这项研究强调了脂肪变性HCC中独特的FA代谢模式,为潜在的治疗靶点提供了有价值的见解。
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 letters
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.
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