Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2– β -Catenin–BRG1 Transcriptional Network-Driven CD47 Expression

Abstract

© 2018 American Society for Microbiology. A gain-of-function mutation in isocitrate dehydrogenase 1 (IDH1) affectsimmune surveillance in gliomas. As elevated CD47 levels are associated with immuneevasion in cancers, its status in gliomas harboring mutant IDH1 (IDH1-MT cells) was investigated.Decreased CD47 expression in IDH1-R132H-overexpressing cells was accompaniedby diminished nuclear β-catenin, pyruvate kinase isoform M2 (PKM2), and TCF4levels compared to those in cells harboring wild-type IDH1 (IDH1-WT cells). The inhibitionof β-catenin in IDH1-WT cells abrogated CD47 expression, β-catenin-TCF4 interaction,and the transactivational activity of β-catenin/TCF4. The reverse effect was observedin IDH1-MT cells upon the pharmacological elevation of nuclear β-catenin levels.Genetic and pharmacological manipulation of nuclear PKM2 levels in IDH1-WT andIDH1-MT cells suggested that PKM2 is a positive regulator of the β-catenin-TCF4 interaction.The Cancer Genome Atlas (TCGA) data sets indicated diminished CD47, PKM2, andβ-catenin levels in IDH1-MT gliomas compared to IDH1-WT gliomas. Also, elevated BRG1levels with mutations in the ATP-dependent chromatin-remodeling site were observedin IDH1-MT glioma. The ectopic expression of ATPase-deficient BRG1 diminished CD47expression as well as TCF4 occupancy on its promoter. Sequential chromatin immunoprecipitation(ChIP-re-ChIP) revealed the recruitment of the PKM2-β-catenin-BRG1-TCF4complex to the TCF4 site on the CD47 promoter. This occupancy translated into CD47transcription, as a diminished recruitment of this complex was observed in glioma cellsbearing IDH1-R132H. In addition to its involvement in CD47 transcriptional regulation,PKM2-β-catenin-BRG1 cross talk affected the phagocytosis of IDH1-MT cells by microglia.