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.