Illuminating the arc of molecular events from chronic hepatic injury and fibrosis through hepatocellular carcinoma (HCC) remains the most fundamental challenge in investigative hepatology The overall goal of this application is to elucidate the role of the KLF6 tumor suppressor in hepatocellular homeostasis, injury and cancer. This goal is based on evidence that: a) Inactivation of KLF6, a zinc finger transcription factor, occurs frequently in HCV-associated HCC. Moreover, overexpression of a KLF6 dominant negative splice form, KLF6SV1, contributes to carcinognesis in advanced human HCC;b) KLF6 +/- mice appear phenotypically normal but have markedly increased tumor size and number after a single dose of the carcinogen DEN. Among its newly uncovered tumor suppressor mechanisms, wild type KLF6 transcriptionally represses the hdm2/mdm2, a ubiquitin ligase that normally promotes proteosomal degradation of the p53 tumor suppressor;c) mice with hepatocyte-specific deletion of KLF6 ('KLF6Hep') develop spontaneous hepatic steatosis and hyperglycemia. One candidate target gene markedly down-regulated by deletion of KLF6 in hepatocytes is glucokinase. Based on these data the revised hypotheses are: 1) KLF6 preserves hepatic homeostasis through transcriptional regulation of key genes controlling hepatic lipid and/or carbohydrate metabolism, including glucokinase;2) KLF6-mediated repression of hdm2/mdm2 is antagonized by KLF6SV1, thereby increasing MDM2- regulated p53 degradation.
Chronic liver disease is a major public health threat, affecting hundreds of millions of individuals worldwide. This proposal examines an important and novel gene, KLF6, that contributes to liver development, growth, balance of carbohydrate and lipid metabolism, repair and hepatocellular carcinoma (HCC), the fifth most common cancer worldwide and third leading cause of cancer death. Thus, insights expected to emerge from these studies could significantly advance our understanding of how to enhance liver regeneration in diseased liver, how to accelerate its repair, and how to diagnose and/or treat HCC at stages where the disease may be curable, improving the lives of patients through the developed and developing world.
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