Valproic acid targets IDH1 mutants through alteration of lipid metabolism

Histone deacetylases (HDACs) are key regulators of various cellular processes, influencing both chromatin remodeling and lipid metabolism in cancer cells. In this study, we demonstrate that valproic acid (VPA), a brain-penetrant anti-seizure drug and HDAC inhibitor, suppresses the growth of IDH1 mutant (IDH1 MT) tumors in both in vitro and in vivo models, with some degree of selectivity for IDH1 MT over wild-type tumors. Interestingly, while VPA upregulated several genes, these genes did not exhibit increased chromatin accessibility at their promoters. In contrast, genes downregulated by VPA showed a correlation with reduced promoter chromatin accessibility. Notably, VPA also inhibited the expression of lipogenic genes, which showed a significant reduction in promoter chromatin accessibility, but only in IDH1 MT glioma cell lines. VPA further suppressed the mTOR pathway and downregulated fatty acid synthase (FASN), a key lipogenic enzyme. Both VPA and the selective FASN inhibitor TVB-2640 altered the lipidome and induced apoptosis specifically in IDH1 MT glioma cells, but not in IDH1 wild-type cells. Our findings also suggest that HDACs regulate lipogenic gene expression, with HDAC6 playing a critical role in the regulation of FASN in IDH1 MT glioma cells. Lastly, we demonstrate that FASN knockdown, either alone or in combination with VPA, significantly enhanced survival in an IDH1 MT primary orthotopic xenograft mouse model. These results highlight the potential of targeting fatty acid metabolism through HDAC and/or FASN inhibition as a novel therapeutic strategy for IDH1 mutant gliomas.