Dysregulated epigenetic factors in non-alcoholic fatty liver disease and triggered liver cancer

Already, almost a quarter of the world's population suffers from non-alcoholic fatty liver (NAFLD) and this problem is steadily increasing. Non-alcoholic steatohepatitis (NASH), the chronic progressive manifestation of NAFLD, is the second most important cause of hepatocellular carcinoma (HCC). NAFLD thus represents a major socio-economic burden on the health care system and is of increasing importance. There are currently no drugs nor therapies that can treat NASH or stop the progression of the disease to HCC. At the same time, treatment options for HCC are limited and many patients show resistance to sorafenib, the only drug currently approved for first-line therapy. Although there have been major advances uncovering the genetic basis for NAFLD and HCC, the epigenetic mechanisms driving HCC remains largely elusive. Nevertheless, recent studies suggest epigenetic manipulation could be a promising approach to prevent the progression of NAFLD and HCC. Pan-Histone deacetylase (Pan-HDAC) inhibitors (e.g. Verinostat, PXD-101, Resminostat) are under clinical trials for HCC therapy. Pan-HDAC inhibitors have side effects and most importantly, others and we have observed that specific genetic knockouts of HDAC (e.g. HDAC3 and HDAC2) induce liver cancer under normal condition. We require more specific and alternate approach to develop therapy against this deadly disease. Epigenetic mechanisms underlying NAFLD progression remain elusive. Here, we are systematically investigating epigenetic factors that regulate NASH and transition to HCC in recently established our diet-induced NASH/HCC mouse models that recapitulate pathophysiological aspects of human NASH/HCC. Employing mass-spectrometry and next generation sequencing, we have identified putative targets that will be characterized and exploited for developing potential therapeutics for this deadly disease.