Oxidative Stress and Epigenetic Instability in Human Hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is a major cause of cancer death, and its development is influenced by the status of inflammation and oxidative stress in the liver. Although oxidative stress might induce genetic changes and play a role in HCC development, many epigenetic alterations have also been reported in this type of tumor, suggesting the importance of epigenetic instability in hepatocarcinogenesis. Epigenetic instability results in 2 types of DNA alterations: hypermethylation of the promoter of tumor suppressor genes (TSGs), and hypomethylation of nonpromoter CpG, such as repetitive elements and satellite DNA. The former causes transcriptional inactivation of TSGs, while the latter reportedly induces chromosomal instability and an abnormal activation of oncogenes as well as mobile genetic elements. Oxidative stress could induce epigenetic instability and inactivate TSGs through the recruitment of the polycomb repressive complex to the promoter sequence carrying DNA damage induced by oxidation. Inflammatory cytokines from immune cells also reportedly induce expression of several histone and DNA modulators. On the other hand, DNA oxidation could lead to activation of DNA repair pathways and affect the binding of methyl cytosine-binding protein to DNA, which could cause DNA hypomethylation. The decrease of the level of methyl group donors also contributes to the alteration in the methylation status. These mechanisms should act in concert and induce epigenetic instability, leading to HCC.