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HNF4A functions as an HCC oncogene or tumor suppressor depending upon the AMPK pathway activity status

ABSTRACT: Background & Aims: Hepatocyte nuclear factor 4A (HNF4A) is a master transcription factor (TF) in hepatocytes that regulates metabolism and differentiation. The mechanism of HNF4A in cancer progression remains unclear due to conflicting results observed in numerous studies. We aimed to address the roles of HNF4A in hepatocellular carcinoma (HCC). Methods: We established the HNF4A overexpression and knocking-down stable cells in HCCLM3 and Huh7, and compared the effects of HNF4A on HCC cells in different glucose supply conditions in vitro and in vivo. Pathway inhibitors treatment and phosphatase activity comparisons were performed for signaling pathway analysis. Gene levels in HCC tissues and the clinical information were collected from TCGA for survival analysis. Multiomics approaches including proteomics, TFRE and ChIP-seq were applied to identify HNF4A target genes. Rescue experiments were performed to verify the functions of the potential target genes. Results: We found HNF4A exhibited tumor-suppressive effects on proliferation and migration of HCC cells in glucose-sufficient conditions but tumor-promotive effects in glucose-insufficient conditions. This diverse functionality of HNF4A was dependent upon the AMPK pathway activity. Similarly, the prognosis predicted by HNF4A was also correlated with AMPKa expression level in HCC patients. The potential HNF4A target genes, including NEDD4 and RPS6KA2, are involved in the diverse functionality of HNF4A in response to AMPK activity status. Conclusions: The glucose supply status could be the potential decisive factor to determine functions of HNF4A on HCC cells. The switch of HNF4A between oncogene and tumor suppressor was determined by AMPK activation status, which was correlated with glucose levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE101553 | GEO | 2019/08/01

REPOSITORIES: GEO

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Project description:The mechanism by which tumor cells resist metabolic stress remains unclear, but many oncogenes are known to regulate this process. Accordingly, metabolic stress is closely associated with tumor metastasis. In this study, gene chip technology showed that RHOF, a member of the Rho GTPase family, is an oncogene that is significantly related to hepatocellular carcinoma (HCC) metastasis; however, it has rarely been reported in tumors. This study was aimed to determine the clinicopathological significance and role of RHOF in HCC progression and investigate the associated mechanisms. The results showed that compared to expression in adjacent non-cancerous tissues, RHOF was frequently upregulated in HCC tumor samples and elevated under conditions of glucose deprivation. RHOF expression was associated with TNM stage, T grade, metastasis status, recurrence, and survival in HCC. RHOF also affected cell morphology and promoted migration, invasion, and epithelial–mesenchymal transition (EMT) of HCC cell lines. Analysis of the underlying mechanism showed that RHOF promoted the Warburg effect by upregulating the expression and function of several glycolytic enzymes in HCC cells. This metabolic shift enhanced HCC cell migration and invasion. Specifically, RHOF exerted tumor-promoting effect by directly interacting with AMP-activated protein kinase (AMPK) and increasing the phosphorylation of AMPK. This subsequently affected RAB3D mRNA stability and led to elevated RAB3D expression, thereby amplifying the Warburg effect and malignant biological behaviors of HCC cells. Therefore, RHOF helps tumor cells resist metabolic stress through modulating the Warburg effect and plays a critical role in promoting HCC cell migration, invasion, and EMT, highlighting its important role in remodeling the metastatic microenvironment and regulating tumor metastasis. RHOF shows potential as a new therapeutic target and prognostic biomarker for HCC. We used microarrays to detail the global programme of gene expression associated with hepatocellular carcinoma metastasis and identified distinct classes of deregulated genes during this process.

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HNF4A functions as an HCC oncogene or tumor suppressor depending upon the AMPK pathway activity status

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