Deciphering <i>KDM8</i> dysregulation and CpG methylation in hepatocellular carcinoma using multi-omics and machine learning

<b>Aim:</b> This study investigates the altered expression and CpG methylation patterns of histone demethylase <i>KDM8</i> in hepatocellular carcinoma (HCC), aiming to uncover insights and promising diagnostics biomarkers. <b>Materials &amp; methods:</b> Leveraging TCGA-LIHC multi-omics data, we employed R/Bioconductor libraries and Cytoscape to analyze and construct a gene correlation network, and LASSO regression to develop an HCC-predictive model. <b>Results:</b> In HCC, <i>KDM8</i> downregulation is correlated with CpGs hypermethylation. Differential gene correlation analysis unveiled a liver carcinoma-associated network marked by increased cell division and compromised liver-specific functions. The LASSO regression identified a highly accurate HCC prediction signature, prominently featuring CpG methylation at cg02871891. <b>Conclusion:</b> Our study uncovers CpG hypermethylation at cg02871891, possibly influencing <i>KDM8</i> downregulation in HCC, suggesting these as promising biomarkers and targets. Changes in gene function can play a role in causing cancer. In this study, we looked at how a specific gene called <i>KDM8</i> behaves in liver cancer. By analyzing a large set of liver cancer samples, we investigated how gene interactions are different in this disease and if they can help predict liver cancer risk. Our results show that the <i>KDM8</i> gene is less active, and its DNA gets chemically modified more often in liver cancer. We also found a group of genes and DNA changes, which are linked to the disease. Using this information, we identified 16 important markers and built a computer model that can accurately predict liver cancer. We found that DNA methylation at a specific spot called cg02871891 is especially important for predicting liver cancer. Overall, our study suggests that high levels of DNA methylation may lead to reduced <i>KDM8</i> activity in liver cancer, which could be important for future research and better diagnostic tools. Integrating multi-omics and ML suggests hypermethylation of cg02871891 potentially downregulates <i>KDM8</i> in HCC. This signature holds promise for advanced diagnostics and treatments. #LiverCancer. Hepatocellular carcinoma (HCC) is a prevalent liver cancer marked by reduced expression of <i>KDM8</i> and associated with low overall survival rates. DNA methylation is an epigenetic mechanism that regulates gene expression. Hypermethylation of CpG sites may lead to the downregulation of <i>KDM8</i>, a phenomenon that requires further investigation. This study examines the relationship between <i>KDM8</i> expression and CpG methylation in HCC by leveraging multi-omics data from TCGA-LIHC and employing advanced bioinformatics techniques to identify regulatory patterns and potential diagnostic biomarkers. Our findings indicate that the downregulation of <i>KDM8</i> in HCC is associated with hypermethylation of specific CpG sites, notably cg02871891 and cg03101936. Differential gene correlation analysis revealed a liver carcinoma-associated network characterized by altered cell division and compromised liver-specific functions. LASSO regression identified an accurate HCC prediction signature prominently featuring CpG methylation at cg02871891. Integrating data from <i>KDM8</i> expression, methylation and ATAC-seq assays suggested that hypermethylation at cg02871891 is linked to restricted chromatin accessibility and reduced gene expression, necessitating further experimental validation. CpG hypermethylation at cg02871891 emerged as a potential epigenetic marker contributing to the downregulation of <i>KDM8</i> in HCC. Further research is warranted to explore the therapeutic potential of targeting cg02871891 and <i>KDM8</i> in HCC.