Depletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4
Abstract Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the und...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-03-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06486-z |
| _version_ | 1797273044694073344 |
|---|---|
| author | Limei Deng Yunbo Di Caiyun Chen Juan Xia Bingxi Lei Ning Li Qingyu Zhang |
| author_facet | Limei Deng Yunbo Di Caiyun Chen Juan Xia Bingxi Lei Ning Li Qingyu Zhang |
| author_sort | Limei Deng |
| collection | DOAJ |
| description | Abstract Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the underlying mechanism remains unclear. In this study, we demonstrated that IGF2BP3 knockdown is detrimental to cell growth and survival in glioma cells. Notably, we discovered that IGF2BP3 regulated ferroptosis by modulating the protein expression level of GPX4 through direct binding to a specific motif on GPX4 mRNA. Strikingly, the m6A modification at this motif was found to be critical for GPX4 mRNA stability and translation. Furthermore, IGF2BP3 knockdown glioma cells were incapable of forming tumors in a mouse xenograft model and were more susceptible to phagocytosis by microglia. Our findings shed light on an unrecognized regulatory function of IGF2BP3 in ferroptosis. The identification of a critical m6A site within the GPX4 transcript elucidates the significance of post-transcriptional control in ferroptosis. |
| first_indexed | 2024-03-07T14:38:55Z |
| format | Article |
| id | doaj.art-867ec091003f4858af05c9dfe9973b6d |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:38:55Z |
| publishDate | 2024-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-867ec091003f4858af05c9dfe9973b6d2024-03-05T20:30:30ZengNature Publishing GroupCell Death and Disease2041-48892024-03-0115311510.1038/s41419-024-06486-zDepletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4Limei Deng0Yunbo Di1Caiyun Chen2Juan Xia3Bingxi Lei4Ning Li5Qingyu Zhang6Laboratory of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical UniversityLaboratory of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical UniversityLaboratory of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical UniversityDepartment of Hematology, Affiliated Hospital of Guangdong Medical UniversityDepartment of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityThe Marine Biomedical Research Institute, Guangdong Medical UniversityLaboratory of Obstetrics and Gynecology, Affiliated Hospital of Guangdong Medical UniversityAbstract Emerging evidence highlights the multifaceted contributions of m6A modifications to glioma. IGF2BP3, a m6A modification reader protein, plays a crucial role in post-transcriptional gene regulation. Though several studies have identified IGF2BP3 as a poor prognostic marker in glioma, the underlying mechanism remains unclear. In this study, we demonstrated that IGF2BP3 knockdown is detrimental to cell growth and survival in glioma cells. Notably, we discovered that IGF2BP3 regulated ferroptosis by modulating the protein expression level of GPX4 through direct binding to a specific motif on GPX4 mRNA. Strikingly, the m6A modification at this motif was found to be critical for GPX4 mRNA stability and translation. Furthermore, IGF2BP3 knockdown glioma cells were incapable of forming tumors in a mouse xenograft model and were more susceptible to phagocytosis by microglia. Our findings shed light on an unrecognized regulatory function of IGF2BP3 in ferroptosis. The identification of a critical m6A site within the GPX4 transcript elucidates the significance of post-transcriptional control in ferroptosis.https://doi.org/10.1038/s41419-024-06486-z |
| spellingShingle | Limei Deng Yunbo Di Caiyun Chen Juan Xia Bingxi Lei Ning Li Qingyu Zhang Depletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4 Cell Death and Disease |
| title | Depletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4 |
| title_full | Depletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4 |
| title_fullStr | Depletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4 |
| title_full_unstemmed | Depletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4 |
| title_short | Depletion of the N 6 -Methyladenosine (m6A) reader protein IGF2BP3 induces ferroptosis in glioma by modulating the expression of GPX4 |
| title_sort | depletion of the n 6 methyladenosine m6a reader protein igf2bp3 induces ferroptosis in glioma by modulating the expression of gpx4 |
| url | https://doi.org/10.1038/s41419-024-06486-z |
| work_keys_str_mv | AT limeideng depletionofthen6methyladenosinem6areaderproteinigf2bp3inducesferroptosisingliomabymodulatingtheexpressionofgpx4 AT yunbodi depletionofthen6methyladenosinem6areaderproteinigf2bp3inducesferroptosisingliomabymodulatingtheexpressionofgpx4 AT caiyunchen depletionofthen6methyladenosinem6areaderproteinigf2bp3inducesferroptosisingliomabymodulatingtheexpressionofgpx4 AT juanxia depletionofthen6methyladenosinem6areaderproteinigf2bp3inducesferroptosisingliomabymodulatingtheexpressionofgpx4 AT bingxilei depletionofthen6methyladenosinem6areaderproteinigf2bp3inducesferroptosisingliomabymodulatingtheexpressionofgpx4 AT ningli depletionofthen6methyladenosinem6areaderproteinigf2bp3inducesferroptosisingliomabymodulatingtheexpressionofgpx4 AT qingyuzhang depletionofthen6methyladenosinem6areaderproteinigf2bp3inducesferroptosisingliomabymodulatingtheexpressionofgpx4 |