De novo lipogenesis pathway is a vulnerability in IDH1 mutant glioma

Abstract

Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-epileptic and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild type tumors. Surprisingly, genes upregulated by VPA showed no change in chromatin accessibility at the promoter, but there was a correlation between VPA downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decrease in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA targeted a key lipogenic gene, fatty acid synthase (FASN), via inhibition of the mTOR pathway and both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find HDACs are involved in the regulation of lipogenic genes and in particular HDAC6 is important for regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in a IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic option in IDH1 mutant gliomas.