Journal
CANCERS
Volume 8, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/cancers8080076
Keywords
non-alcoholic fatty liver disease; hepatocellular carcinoma; Wnt; beta-catenin; epigenetics; DNA methylation; histone modification; microRNA; HDAC8
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Funding
- Hong Kong Research Grants Council [C4017-14G, 14102914]
- National Natural Science Foundation of China [373492, 81302167, 81522030, 91439132]
- National Program on Key Basic Research of China (973 Program) [2015CB553705]
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Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/beta-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/beta-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding -catenin protein) or other antagonists targeting Wnt/beta-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal -catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/beta-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
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