Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity

The majority of oligodendrogliomas (ODGs) exhibit combined losses of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH1-R132H or IDH2-R172K). Approximately 70% of ODGs with 1p19q co-deletions harbor somatic mutations in the Capicua Transcriptional Repressor (CIC) gene on chromoso...

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Published in:Oncotarget 2014-09, Vol.5 (17), p.7960-7979
Main Authors: Chittaranjan, Suganthi, Chan, Susanna, Yang, Cindy, Yang, Kevin C, Chen, Vincent, Moradian, Annie, Firme, Marlo, Song, Jungeun, Go, Nancy E, Blough, Michael D, Chan, Jennifer A, Cairncross, J Gregory, Gorski, Sharon M, Morin, Gregg B, Yip, Stephen, Marra, Marco A
Format: Article
Language:English
Subjects:
Blotting, Western
Brain Neoplasms - genetics
Brain Neoplasms - metabolism
Cell Line, Tumor
Glutarates - metabolism
Humans
Immunoprecipitation
Isocitrate Dehydrogenase - genetics
Mass Spectrometry
Mutation
Oligodendroglioma - genetics
Oligodendroglioma - metabolism
Repressor Proteins - genetics
Research Paper
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Summary:The majority of oligodendrogliomas (ODGs) exhibit combined losses of chromosomes 1p and 19q and mutations of isocitrate dehydrogenase (IDH1-R132H or IDH2-R172K). Approximately 70% of ODGs with 1p19q co-deletions harbor somatic mutations in the Capicua Transcriptional Repressor (CIC) gene on chromosome 19q13.2. Here we show that endogenous long (CIC-L) and short (CIC-S) CIC proteins are predominantly localized to the nucleus or cytoplasm, respectively. Cytoplasmic CIC-S is found in close proximity to the mitochondria. To study wild type and mutant CIC function and motivated by the paucity of 1p19q co-deleted ODG lines, we created HEK293 and HOG stable cell lines ectopically co-expressing CIC and IDH1. Non-mutant lines displayed increased clonogenicity, but cells co-expressing the mutant IDH1-R132H with either CIC-S-R201W or -R1515H showed reduced clonogenicity in an additive manner, demonstrating cooperative effects in our assays. Expression of mutant CIC-R1515H increased cellular 2-Hydroxyglutarate (2HG) levels compared to wild type CIC in IDH1-R132H background. Levels of phosphorylated ATP-citrate Lyase (ACLY) were lower in cell lines expressing mutant CIC-S proteins compared to cells expressing wild type CIC-S, supporting a cytosolic citrate metabolism-related mechanism bof reduced clonogenicity in our in vitro model systems. ACLY or phospho-ACLY were similarly reduced in CIC-mutant 1p19q co-deleted oligodendroglioma patient samples.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2401