Histone methylation in pre-cancerous liver diseases and hepatocellular carcinoma: recent overview

Abstract

Hepatocellular carcinoma (HCC) is the prevalent form of liver cancer in adults and the fourth most common cause of cancer-related death worldwide. HCC predominantly arises in the context of cirrhosis as a result of chronic liver disease, injury and inflammation. Full-blown HCC has poor prognosis because it is highly aggressive and resistant to therapy. Consequently, interventions that can prevent or restrain HCC emergence from pre-cancerous diseased liver are a desirable strategy. Histone methylation is a dynamic, reversible epigenetic modification involving the addition or removal of methyl groups from lysine, arginine or glutamine residues. Aberrant activity of histone methylation writers, erases and readers has been implicated in several cancer types, including HCC. In this review, we provide an overview of research on the role of histone methylation in pre-cancerous and cancerous HCC published over the last 5 years. In particular, we present the evidence linking environmental factors such as diet, viral infections and carcinogenic agents with dysregulation of histone methylation during liver cancer progression with the aim to highlight future therapeutic possibilities.

Keywords: Environmental carcinogens; Hepatocellular carcinoma; Histone demethylases; Histone methyltransferases; Non-alcoholic fatty liver disease; Viral hepatitis.

Fig. 1

Dietary patterns that influence gene expression through histone methyltransferases and demethylases in NALFD progression. Top (blue) panel shows epigenetic modifiers that promote the progression of NAFLD, and bottom (orange) panel shows protective epigenetic modifiers that prevent the progression of NAFLD

Fig. 2

Regulation of cccDNA by histone methylation. HBV has a relaxed DNA genome that within the nucleus is transformed into cccDNA. The cccDNA persists within infected cells to act as template for production of viral particles. The rate of transcription of viral particles from the cccDNA is regulated among other factors by histone methylation and the activity of methyltransferases and demethylases

Fig. 3

Examples of methyltransferases and demethylases deregulated in HCC and their functions in disease progression

Fig. 4

Histone methylation as a target for preventing progression of diseased liver to HCC. Exposure of healthy liver to agents such as unhealthy diet and viruses can cause chronic liver disease, with histone methylation implicated in this step. Targeting histone methylation in pre-cancerous disease liver, for example through the use of selective chemical inhibitors or medications, can potentially prevent or delay progression to HCC that is resistant to therapies