Mutant IDH disables p53 tumor suppression [CUT&RUN]

p53 prevents tumor initiation and progression by adapting cell fate via transcriptional regulation of target gene networks. Here, we find that cancer associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes outgrowth of cancer cells with transcriptionally active, wild type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG) dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression. Mutant IDH interferes with the expression of pro-apoptotic p53 targets, including the death ligand receptor Fas that enables p53 dependent liver tumor regressions. Pharmacological inhibition of mutant IDH in TP53 wildtype cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy induced apoptosis. Therefore, we implicate disruption of p53 target gene regulation as a reversable, oncogenic feature of cancer associated IDH mutations.