HNF4A functions as a hepatocellular carcinoma oncogene or tumor suppressor depending upon the AMPK pathway activity status

IF 9.1 1区 医学 Q1 ONCOLOGY
Zhaoyu Qin , Yan Li , Xiexiang Shao , Kai Li , Yihe Bai , Bing Wang , Fahan Ma , Wenhao Shi , Lei Song , Aojia Zhuang , Fuchu He , Chen Ding , Wenjun Yang
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引用次数: 0

Abstract

Cancer cells frequently undergo energy metabolic stress induced by the increased dynamics of nutrient supply. Hepatocyte nuclear factor 4A (HNF4A) is a master transcription factor (TF) in hepatocytes that regulates metabolism and differentiation. However, the mechanism underlying how HNF4A functions in cancer progression remains unclear due to conflicting results observed in numerous studies. To address the roles of HNF4A in hepatocellular carcinoma (HCC), we investigated the regulatory functions of HNF4A in HCC cells under different glucose supply conditions. We found that HNF4A exhibited tumor-suppressive effects on the proliferation and migration of HCC cells in glucose-sufficient conditions and tumor-promotive effects on HCC cells in glucose-insufficient conditions. Further investigation revealed that this diverse function of HNF4A was dependent upon the AMPK pathway activity. Similarly, the prognosis predicted by HNF4A was also correlated with whether the AMPKa expression levels were low or high in clinical HCC patients. Multiomics approaches consisting of proteomics and ChIP-seq revealed that key HNF4A target genes, including NEDD4 and RPS6KA2, are involved in the diverse function of HNF4A in HCC in response to the AMPK activity status. Specifically, HNF4A could bind to the promoter region of NEDD4 and RPS6KA2, and upregulating their expression. Our study has demonstrated the relationship between and synergism of AMPK and HNF4A in the progression of HCC under diverse nutrient conditions.
HNF4A作为肝细胞癌癌基因或肿瘤抑制因子的功能取决于AMPK通路的活性状态
由于营养供应的动态增加,癌细胞经常经历能量代谢应激。肝细胞核因子4A (HNF4A)是调节肝细胞代谢和分化的主转录因子(TF)。然而,由于许多研究中观察到的结果相互矛盾,HNF4A在癌症进展中的作用机制尚不清楚。为了研究HNF4A在肝细胞癌(HCC)中的作用,我们研究了不同葡萄糖供应条件下HNF4A在HCC细胞中的调节功能。我们发现,在葡萄糖充足的条件下,HNF4A对HCC细胞的增殖和迁移具有抑瘤作用,在葡萄糖不足的条件下,HNF4A对HCC细胞具有促瘤作用。进一步的研究表明,HNF4A的这种多样化功能依赖于AMPK通路的活性。同样,HNF4A预测的预后也与AMPKa在临床HCC患者中的表达水平高低相关。由蛋白质组学和ChIP-seq组成的多组学方法显示,包括NEDD4和RPS6KA2在内的关键HNF4A靶基因参与了HNF4A在HCC中响应AMPK活性状态的多种功能。具体来说,HNF4A可以结合NEDD4和RPS6KA2的启动子区域,上调它们的表达。我们的研究证明了AMPK和HNF4A在不同营养条件下HCC进展中的关系和协同作用。
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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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