DNA methylation and gene expression profiling highlight retinol metabolism's vital role in Hepatocellular carcinoma development

Abstract

Abstract Purpose Abnormal DNA methylation patterns play a critical role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms associated with these aberrantly methylated genes remain unclear. In this study, we aimed to comprehensively investigate the methylation-driven deregulated gene expressions in HCC using a large cohort of patients with diverse clinical characteristics. Methods Whole-genome bisulfite sequencing (WGBS) and RNA sequencing techniques were used to assess the methylation and gene expression profiles of HCC tissue and normal adjacent tissues (NATs). The potential function of candidate genes was then investigated using single cell RNA-seq (sc-RNA seq) data. Results We identified 132,773 differentially methylated regions (DMRs) and 4,322 differentially expressed genes (DEGs) between HCC and NATs. Integrated DNA methylation and RNA-seq data obtained 987 methylation-driven candidates, including 970 upregulated and 17 downregulated genes. Four retinol metabolic pathway genes, ADH1A, CYP2A6, CYP2C8, and CYP2C19, were found as hyper-downregulated genes, whose expressions could stratify HCC into three subgroups with distinct survival outcomes, immune cell infiltration, and tumor microenvironments. Validation of these findings in an independent dataset confirmed the high concordance and potential prognostic value of these genes. Sc-RNA seq data revealed the low expression of these genes in immune cells and highlighted their role in promoting malignant cell proliferation and migration. Conclusion This study provides an insight into the molecular characteristics of HCC, unraveling the involvement of retinol metabolism-related genes in HCC development and progression. These findings have implications for HCC diagnosis, prognosis prediction, and the development of therapeutic targets.