Abstract
BackgroundEpigenetics regulate gene expression without altering the DNA sequence. Epigenetics targeted chemotherapeutic approach can be used to overcome treatment resistance and low response rate in HCC. However, a comprehensive review of genomic data was carried out to determine the role of epigenesis in the tumor microenvironment (TME), immune cell-infiltration characteristics in HCC is still insufficient.MethodsThe association between epigenetic-related genes (ERGs), inflammatory response-related genes (IRRGs) and CRISPR genes was determined by merging genomic and CRISPR data. Further, characteristics of immune-cell infiltration in the tumor microenvironment was evaluated.ResultsNine differentially expressed genes (ANP32B, ASF1A, BCORL1, BMI1, BUB1, CBX2, CBX3, CDK1, and CDK5) were shown to be independent prognostic factors based on lasso regression in the TCGA-LIHC and ICGC databases. In addition, the results showed significant differences in expression of PDCD-1 (PD-1) and CTLA4 between the high- and low-epigenetic score groups. The CTRP and PRISM-derived drug response data yielded four CTRP-derived compounds (SB-743921, GSK461364, gemcitabine, and paclitaxel) and two PRISM-derived compounds (dolastatin-10 and LY2606368). Patients with high ERGs benefited more from immune checkpoint inhibitor (ICI) therapy than patients with low ERGs. In addition, the high ERGs subgroup had a higher T cell exclusion score, while the low ERGs subgroup had a higher T cell dysfunction. However, there was no difference in microsatellite instability (MSI) score among the two subgroups. Further, genome-wide CRISPR-based loss-of function screening derived from DepMap was conducted to determine key genes leading to HCC development and progression. In total, 640 genes were identified to be essential for survival in HCC cell lines. The protein-protein interaction (PPI) network demonstrated that IRRGs PSEN1 was linked to most ERGs and CRISPR genes such as CDK1, TOP2A, CBX2 and CBX3. ConclusionEpigenetic alterations of cancer-related genes in the tumor microenvironment play a major role in carcinogenesis. This study showed that epigenetic-related novel biomarkers could be useful in predicting prognosis, clinical diagnosis, and management in HCC.
Highlights
Epigenetics regulate gene expression without altering the DNA sequence
RNA-seq analyses based on the adequate tumor purity and the tumor purity estimates by single sample gene set enrichment analysis for tumor tissue samples from Hepatocellular carcinoma (HCC)
We hypothesized that cluster A could affect epigenetics and other cancer-related processes, resulting in a poor prognosis
Summary
Epigenetics regulate gene expression without altering the DNA sequence. Epigenetics targeted chemotherapeutic approach can be used to overcome treatment resistance and low response rate in HCC. Hepatocellular carcinoma (HCC) is a highly aggressive malignant disease. It is the fastest-growing cause of cancerrelated death worldwide [1]. The molecular pathogenesis of HCC is still not clear [2, 3]. Early-stage HCC is curable by resection, liver transplantation or ablation. Recent years have seen the advent of the role of immune checkpoint inhibitors has been investigated and the PD-L1 inhibitor atezolizumab in combination with bevacizumab has reported unprecedented results in HCC patients [6,7,8]. There is an urgent need to investigate the molecular pathogenesis and regulatory network of HCC to discover therapeutic targets and develop effective drugs. There is a need to establish a model for predicting HCC prognosis
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