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

Chittaranjan, Suganthi and Chan, Susanna and Yang, Cindy and Yang, Kevin C. and Chen, Vincent and Moradian, Annie and Firme, Marlo and Song, Jungeun and Go, Nancy E. and Blough, Michael D. and Chan, Jennifer A. and Cairncross, J. Gregory and Gorski, Sharon M. and Morin, Gregg B. and Yip, Stephen and Marra, Marco A. (2014) Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. Oncotarget, 5 (17). pp. 7960-7979. ISSN 1949-2553. PMCID PMC4202173. https://resolver.caltech.edu/CaltechAUTHORS:20140915-092839728

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2401PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202173/PubMed CentralArticle
https://doi.org/10.18632/oncotarget.2401DOIArticle
ORCID:
AuthorORCID
Moradian, Annie0000-0002-0407-2031
Marra, Marco A.0000-0001-7146-7175
Additional Information:© 2014 Impact Journals, LLC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: April 01, 2014 Accepted: August 26, 2014 Published: August 27, 2014. We thank the DNA sequencing, library construction, and biospecimen cores at the BC Cancer Agency Genome Sciences Centre for technical support. We thank Robyn Roscoe for expert Project Management support. The authors thank Chandra Lebovitz and Dr. Jill Mwenifumbo for helpful edits and comments on the manuscript. We thank Drs. Carol MacKintosh (University of Dundee, Scotland, UK) and Huda Y. Zoghbi (Howard Hughes Medical Institute, Houston, Texas) for providing us with CIC constructs. We thank Dr. G. Dawson (The University of Chicago, Illinois, USA) for providing us the HOG glioma cell line. We thank Drs. Andreas von Deimling and Joerg Balss (DKFZ - German Cancer Research Center, Heidelberg, Germany) for providing us with HGDH enzyme for 2HG enzymatic assays. MAM acknowledges the support of the Canada Research Chairs program and the BC Cancer Foundation, and is especially grateful to Ms. Donna Anderson for her generosity in supporting this project. SMG gratefully acknowledges support from CIHR MOP-78882 and a CIHR New Investigator award. GBM acknowledges support from the BC Cancer Foundation. JGC is supported by the Alberta Cancer Foundation, the Terry Fox Research Institute and Foundation, and the generosity of the family of Clark H. Smith. SY acknowledges generous support from BrainCareBC and a VCHRI Mentored Clinician Scientist Award.
Funders:
Funding AgencyGrant Number
Canada Research Chairs programUNSPECIFIED
BC Cancer FoundationUNSPECIFIED
Donna AndersonUNSPECIFIED
Canadian Institutes of Health Research (CIHR)MOP-78882
BC Cancer FoundationUNSPECIFIED
Alberta Cancer FoundationUNSPECIFIED
Terry Fox Research Institute and FoundationUNSPECIFIED
The Family of Clark H. SmithUNSPECIFIED
BrainCareBCUNSPECIFIED
Vancouver Coastal Health Research Institute (VCHRI)UNSPECIFIED
Subject Keywords:CIC; IDH1; ACLY; citrate; 2HG; Oligodendroglioma
Issue or Number:17
PubMed Central ID:PMC4202173
Record Number:CaltechAUTHORS:20140915-092839728
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140915-092839728
Official Citation:Chittaranjan, S., Chan, S., Yang, C., Yang, K., Chen, V., Moradian, A., Firme, M., Song, J., Go, N., Blough, M., Chan, J., Cairncross, G., Gorski, S., Morin, G., Yip, S., & Marra, M. (2014). Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. Oncotarget, 5. Retrieved from http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=2401
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:49690
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:17 Sep 2014 18:51
Last Modified:09 Mar 2020 13:19

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