UCLA

Missense mutation in the gene isocitrate dehydrogenase (IDH) rewires the metabolic and chromatin landscape of IDH mutant (MT) gliomas making them distinct from IDH wildtype (WT) gliomas. There is an intimate relationship between the epigenome and lipidome. In this study, we discovered valproic acid (VPA) a broad-spectrum anti-epileptic and histone deacetylase (HDAC) inhibitor modifies both the chromatin and the lipidome of IDH MT gliomas. We find that VPA significantly upregulates transcription of genes, but this does not necessarily correlate with increased overall chromatin accessibility. We identified a subset of lipogenic enzymes that are all downregulated with VPA treatment and show loss of chromatin accessibility around their promoter region. We characterized inhibition of one those enzymes FASN and show that both VPA treatment and FASN inhibition remodels the lipidome of IDH MT glioma and this remodeling is distinct from what we see in a IDH WT cell line. Lastly, due to metabolic flexibility of IDH MT glioma cells we propose combination of VPA with a FASN inhibitor might be a better way of targeting IDH MT gliomas.