Prognostic hub gene CBX2 drives a cancer stem cell-like phenotype in HCC revealed by multi-omics and multi-cohorts.

Hepatocellular carcinoma (HCC) is a malignant tumor with a high prevalence and fatality rate. CBX2 has been demonstrated to impact the development and advancement of various cancers, albeit it has received limited attention in relation to HCC. In this study, CBX2 and CEP55 were screened out with the refined triple regulatory networks constructed by total RNA-seq datasets (TCGA-LIHC, GSE140845) and a robust prognostic model. Aberrantly higher expression levels of and in HCC may be caused by CNV alterations, promoter hypo-methylation, open chromatin accessibility, and greater active marks such as H3K4me3, H3K4me1, and H3K27ac. Functionally, , which was highly correlated with CD44, shaped a cancer stem cell-like phenotype by positively regulating cell-cycle progression, proliferation, invasion, metastasis, wound healing, and radiation resistance, revealed by combining bulk RNA-seq and scRNA-seq datasets. knockdown validated its role in affecting the cell cycle. Importantly, we revealed CBX2 could activate gene by cooperating with co-regulators or not rather than a recognizer of the repressive mark H3K27me3. For instance, we uncovered CBX2 bound to promoter of and to augment their expressions. showed a highly positive correlation with at pan-cancer level. In addition, and may enhance extracellular matrix reprograming via cancer-associated fibroblast. Surprisingly, patients with high expression of or exhibited a higher response to immunotherapy, indicating that and may be promising therapeutic targets for HCC patients.