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Hepatocellular carcinoma (HCC) is the third most common cause of death for cancer patients globally, with an overall 5-year survival rate of only 16%. The molecular mechanisms leading to malignant progression of HCC patients remain largely unclear. Hepatocyte nuclear factor 4α (HNF4α) functions as a tumor-suppressive transcription factor (TF) in HCC. In this study, we aimed to identify functional HCC susceptibility single nucleotide polymorphisms (SNPs) in HNF4α-binding sites throughout the human genome. We identified 1274 HNF4α-binding site polymorphisms via a genome-wide screening using TUIFGA (the updated integrative functional genomics approach), which we previously developed to recognize cancer susceptibility SNPs within genome-wide TF-binding sites. Among these SNPs, the  DEAF1  rs11246280 SNP was significantly associated with HBV-related HCC susceptibility in several case-control studies. Importantly, the rs11246280 SNP could interrupt HNF4α binding to the  DEAF1  promoter and enhance  DEAF1  expression. Oncogenic TF DEAF1 binds to the  SLC38A3  promoter, elevates glutamine transporter SLC38A3 expression, enhances influx of glutamine and GSH production, leads to reduced ROS levels in cells and, thereby, promotes HCC progression. Our findings highlighted the role of  DEAF1  during HCC development via maintaining redox balance, which sheds light on the development of novel cancer therapeutics.

Integrated functional genomics-identified DEAF1 in oxidative stress and hepatocellular carcinoma development