CIC reduces xCT/SLC7A11 expression and glutamate release in glioma

Jong Whi Park, Omer Kilic, Minh Deo, Kevin Jimenez-Cowell, Engin Demirdizen, Hyunggee Kim, Şevin Turcan

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Capicua (CIC) is an important downstream molecule of RTK/RAS/MAPK pathway. The regulatory mechanism of CIC underlying tumorigenesis in oligodendroglioma, where CIC is frequently mutated, has yet to be fully elucidated. Using patient-derived glioma lines, RNA-sequencing and bioinformatic analysis of publicly available databases, we investigated how CIC loss- or gain-of-function regulates its downstream targets, cell proliferation and glutamate release. Our results indicate an increased frequency of CIC truncating mutations in oligodendroglioma during progression. In vitro, CIC modulation had a modest effect on cell proliferation in glioma lines, and no significant changes in the expression of ETV1, ETV4 and ETV5. Transcriptional repression of known CIC targets was observed in gliomas expressing non-phosphorylatable CIC variant on Ser173 which was unable to interact with 14-3-3. These data outline a mechanism by which the repressor function of CIC is inhibited by 14-3-3 in gliomas. Using transcriptional profiling, we found that genes related to glutamate release were upregulated because of CIC depletion. In addition, loss of CIC leads to increased extracellular glutamate. Consistent with this, CIC restoration in an oligodendroglioma line reduced the levels of extracellular glutamate, neuronal toxicity and xCT/SLC7A11 expression. Our findings may provide a molecular basis for the prevention of glioma-associated seizures.

Original languageEnglish
Article number13
JournalActa neuropathologica communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2023 Dec

Bibliographical note

Funding Information:
We thank members of the Turcan laboratory for helpful discussions and technical assistance. We thank the Genomics and Proteomics Core Facility (GPCF) at the DKFZ for providing next-generation sequencing (NGS) services and Schneider Martin at MS-Based Protein Analysis Core Facility.

Funding Information:
Open Access funding enabled and organized by Projekt DEAL, Deutsche Forschungsgemeinschaft within the funding program "Open Access Publikationskosten“, and Heidelberg University. This research was supported by the German Cancer Aid, Max Eder Program grant number 70111964 (S.T.), Oligo Nation and Operation Oligo Cure (S.T), and Fritz-Thyssen Stiftung (S.T.). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2022R1F1A1063909).

Publisher Copyright:
© 2023, The Author(s).

Keywords

  • Capicua
  • Glutamate
  • Neuronal toxicity
  • Oligodendroglioma
  • xCT/SLC7A11

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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