Friday, May 9, 2025
5/9/2025
Jumonji enzyme action in hepatocellular carcinoma onset - Patients with fatty liver disease have a high risk of progressing to liver cancer, including hepatocellular carcinoma. At the molecular level, two major changes occur in hepatocytes caused by the accumulation of fat in the liver: a switch in energy metabolism, based on mitochondria disfunction and altered TCA cycle flux, and abnormal epigenetic activities, including higher expression of chromatin modifying enzymes. However, the connection between aberrant hepatocyte metabolism and aberrant epigenetic activities in the non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) progression has not been defined, nor therapeutically exploited to combat the onset of HCC. We propose to do so in this application. We will focus on establishing metabolic biomarkers and targeting metabolic/epigenetic co-vulnerabilities during HCC development. The rationale for this approach is that oncogenic epigenetic Jumonji histone demethylase enzymes, chromatin modifiers upregulated in HCC which delete histone methylation marks, use TCA metabolite alpha- ketoglutarate (2-OG) as a co-substrate for catalysis. Indeed, not only is 2-OG a co-substrate for these enzymes but succinate and fumarate can compete with 2-OG for binding, and thus act as inhibitors of Jumonji activity. Current Jumonji inhibitors we and other have developed work by competing with 2-OG. This presents an enormous opportunity in the context of fatty liver disease progressing to HCC, since this progression thus establishes new metabolic vulnerabilities with targetable epigenetic consequences. We hypothesize that altered cellular TCA metabolism in fatty livers triggers aberrant Jumonji KDM histone demethylase levels/activity before HCC onset and that this pro-oncogenic event is targetable through small molecule inhibitors of Jumonji enzymes that compete with 2-OG, to prevent HCC development. We will test this hypothesis by measuring 2-OG related metabolites in the liver and the blood during the NAFLD to HCC progression to identify metabolits that correlate with response to Jumonji inhibition (aim 1, biomarker focus) and by evaluating the efficacy of three available Jumonji inhibitors to prevent or slow down the progression of NAFLD to NASH and to HCC in vivo (aim 2, therapeutic focus). We will use DIAMOND mice as our in vivo model since they recapitulate the human NAFLD, NASH to HCC continuum faithfully, are well characterized, and spontaneously develop HCC within a year. Our studies will inform future personalized medicine applications in the prevention and treatment of hepatocellular carcinoma, making this proposal highly clinically relevant, timely, and potentially transformational.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).