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

Molecular and Cellular Biology
Pruthvi GowdaEllora Sen

Abstract

A gain-of-function mutation in isocitrate dehydrogenase 1 (IDH1) affects immune surveillance in gliomas. As elevated CD47 levels are associated with immune evasion in cancers, its status in gliomas harboring mutant IDH1 (IDH1-MT cells) was investigated. Decreased CD47 expression in IDH1-R132H-overexpressing cells was accompanied by diminished nuclear β-catenin, pyruvate kinase isoform M2 (PKM2), and TCF4 levels compared to those in cells harboring wild-type IDH1 (IDH1-WT cells). The inhibition of 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 observed in IDH1-MT cells upon the pharmacological elevation of nuclear β-catenin levels. Genetic and pharmacological manipulation of nuclear PKM2 levels in IDH1-WT and IDH1-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, and β-catenin levels in IDH1-MT gliomas compared to IDH1-WT gliomas. Also, elevated BRG1 levels with mutations in the ATP-dependent chromatin-remodeling site were observed in IDH1-MT glioma. The ectopic expression of ATPase-deficient BRG1 diminished ...Continue Reading

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Citations

May 10, 2020·Cancer Metastasis Reviews·Zheng ZhongBabita Madan
Jan 11, 2020·Frontiers in Immunology·Elena Martin-OrozcoMaria Ayala-San Nicolas
Aug 28, 2020·Drug Design, Development and Therapy·Yihan SunJianhua Zhou
Dec 18, 2020·Frontiers in Immunology·Jinyang HuBaofeng Wang
Sep 30, 2021·Nature Reviews. Cancer·Brian M AndersenFrancisco J Quintana
May 28, 2019·Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology·Rina Fujiwara-TaniHiroki Kuniyasu
Oct 16, 2021·Journal of Cell Science·Shruti PatrickEllora Sen

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