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CIC reduces xCT/SLC7A11 expression and glutamate release in glioma
Jong-Whi Park1,2, Omer Kilic3, Minh Deo3
1Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 460, 69120, Heidelberg, Germany. jpark@gachon.ac.kr.
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.
Insights
Loss of Capicua (CIC) function in oligodendroglioma increases extracellular glutamate, potentially explaining glioma-associated seizures. Restoring CIC reduces glutamate levels and neuronal toxicity.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Genetics
Background:
- Capicua (CIC) is a downstream target of the RTK/RAS/MAPK pathway, frequently mutated in oligodendroglioma.
- The precise role of CIC regulation in oligodendroglioma tumorigenesis remains unclear.
Purpose of the Study:
- To investigate the regulatory mechanisms of CIC in oligodendroglioma.
- To determine how CIC loss- or gain-of-function affects downstream targets, cell proliferation, and glutamate release.
Main Methods:
- Utilized patient-derived glioma cell lines.
- Performed RNA-sequencing and bioinformatic analysis of public databases.
- Investigated CIC modulation effects on cell proliferation and gene expression.
Main Results:
- CIC truncating mutations are more frequent in progressive oligodendroglioma.
- CIC depletion upregulates genes involved in glutamate release, increasing extracellular glutamate.
- CIC restoration reduces extracellular glutamate, neuronal toxicity, and xCT/SLC7A11 expression.
Conclusions:
- CIC repressor function is inhibited by 14-3-3 interaction in gliomas.
- CIC loss contributes to increased extracellular glutamate, offering a potential target for preventing glioma-associated seizures.
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