Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity
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Suganthi Chittaranjan1, Susanna Chan1, Cindy Yang1, Kevin C. Yang1, Vincent Chen1, Annie Moradian1,2, Marlo Firme1, Jungeun Song1, Nancy E. Go1,3, Michael D. Blough4,5,8, Jennifer A. Chan5,7,8, J. Gregory Cairncross4,5,8, Sharon M. Gorski1,3, Gregg B. Morin1,9, Stephen Yip6 and Marco A. Marra1,9
1 Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada
2 California Institute of Technology, Beckman Institute, Pasadena, CA, USA
3 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
4 Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
5 Southern Alberta Cancer Research Institute, University of Calgary, Calgary, AB, Canada
6 Department of Pathology & Laboratory Medicine Vancouver General Hospital, Vancouver, BC, Canada
7 Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
8 Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, AB, Canada
9 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
Marco A. Marra, email:
Keywords: CIC / IDH1 / ACLY / citrate / 2HG / Oligodendroglioma
Received: April 01, 2014 Accepted: August 26, 2014 Published: August 27, 2014
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 of reduced clonogenicity in our in vitro model systems. ACLY or phospho-ACLY were similarly reduced in CIC-mutant 1p19q co-deleted oligodendroglioma patient samples.
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