Abstract
The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic “scarring” of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome.
Highlights
Hepatocellular Carcinoma (HCC) represents the fifth-most common cancer worldwide and the second cause of cancer death in men, and its incidence has been increasing over the past few decades [1,2]
While direct acting antivirals (DAAs) therapy for Hepatitis C virus (HCV) efficiently eradicates the infection, sustained virological response (SVR) following anti-HCV treatment does not eliminate the risk for Hepatocellular carcinoma (HCC) development
Our discoveries provide an insight into the outcomes of HCV infection and HCC development, following sustained virological responses (SVR), and novel approaches for its prevention
Summary
Hepatocellular Carcinoma (HCC) represents the fifth-most common cancer worldwide and the second cause of cancer death in men, and its incidence has been increasing over the past few decades [1,2]. Its prognosis and survival rates are poor and treatment options are very limited [1]. Liver transplantation is the most effective treatment, and the only drug that prolongs survival by an average of 3 months is sorafenib [3]. HCC is induced by a number of well recognized etiological agents, mainly Hepatitis C virus (HCV) infection in western countries [1]. HCV is a major public health problem with over 71 million people infected worldwide and at risk for developing life-threatening liver diseases [4]. The mechanisms involved in viral persistence leading to HCC are not fully understood
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