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The effect of K458R mutation of HNF4A on HCC

ABSTRACT: To investigate the inhibitory effect of K458R mutation of HNF4A on HCC, we established Huh-7 xenografts treated with Ad-GFP, Ad-HNF4A or Ad-K458R. We then performed gene expression profiling analysis using data obtained from RNA-seq of three groups of Huh-7 xenografts treated with adenovirus.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225329 | GEO | 2023/02/20

REPOSITORIES: GEO

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The effect of K458R mutation of HNF4A on HCC

Project description:The effect of K458R mutation of HNF4A on HCC

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

Project description: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.

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