METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression
Abstract Radiotherapy is one of the main treatment modalities for advanced hepatocellular carcinoma (HCC). Ferroptosis has been shown to promote the radiosensitivity of HCC cells, but it remains unclear whether epigenetic regulations function in this process. In this study, we found that the overexp...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07317-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544236548227072 |
|---|---|
| author | Chen Zhang Tianpeng Yang Hanbin Chen Xiaofeng Ding Huajian Chen Zhenzhen Liang Yinlong Zhao Shumei Ma Xiaodong Liu |
| author_facet | Chen Zhang Tianpeng Yang Hanbin Chen Xiaofeng Ding Huajian Chen Zhenzhen Liang Yinlong Zhao Shumei Ma Xiaodong Liu |
| author_sort | Chen Zhang |
| collection | DOAJ |
| description | Abstract Radiotherapy is one of the main treatment modalities for advanced hepatocellular carcinoma (HCC). Ferroptosis has been shown to promote the radiosensitivity of HCC cells, but it remains unclear whether epigenetic regulations function in this process. In this study, we found that the overexpression of METTL3 was associated with poor prognosis. Knockdown of METTL3 promoted radiosensitivity of HCC by inducing ferroptosis. Mechanistically, METTL3 targeted adenine (+1795) on the SLC7A11 mRNA, and the m6A reader IGF2BP2 promoted SLC7A11 mRNA stability by recognizing and binding to the m6A site. Additionally, METTL3 decreased the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 axis. Furthermore, in vivo studies showed that HCC models with low METTL3/IGF2BP2 expression have higher radiosensitivity. In conclusion, our study suggests that METTL3 regulates the stability of SLC7A11 mRNA in an m6A/IGF2BP2-dependent manner and the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 pathway, both of which require the m6A methyltransferase activity of METTL3. METTL3 or IGF2BP2 may be promising targets for radiotherapy of HCC. |
| format | Article |
| id | doaj-art-74a1d0e64d3540debb5a824f4c2c5e8b |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-74a1d0e64d3540debb5a824f4c2c5e8b2025-01-12T12:41:48ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111810.1038/s41419-024-07317-xMETTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expressionChen Zhang0Tianpeng Yang1Hanbin Chen2Xiaofeng Ding3Huajian Chen4Zhenzhen Liang5Yinlong Zhao6Shumei Ma7Xiaodong Liu8School of Public Health, Wenzhou Medical University, the first affiliated hospital of Wenzhou Medical UniversitySchool of Public Health, Wenzhou Medical Universitythe first affiliated hospital of Wenzhou Medical UniversitySchool of Public Health, Wenzhou Medical UniversitySchool of Public Health, Wenzhou Medical UniversitySchool of Public Health, Wenzhou Medical University, School of Public Health, Xinxiang Medical UniversityDepartment of Nuclear Medicine, The Second Norman Bethune Hospital of Jilin UniversitySchool of Public Health, Wenzhou Medical University; South Zhejiang Institute of Radiation Medicine and Nuclear TechnologySchool of Public Health, Wenzhou Medical University; Key Laboratory of Watershed Science and Health of Zhejiang Province, Wenzhou Medical UniversityAbstract Radiotherapy is one of the main treatment modalities for advanced hepatocellular carcinoma (HCC). Ferroptosis has been shown to promote the radiosensitivity of HCC cells, but it remains unclear whether epigenetic regulations function in this process. In this study, we found that the overexpression of METTL3 was associated with poor prognosis. Knockdown of METTL3 promoted radiosensitivity of HCC by inducing ferroptosis. Mechanistically, METTL3 targeted adenine (+1795) on the SLC7A11 mRNA, and the m6A reader IGF2BP2 promoted SLC7A11 mRNA stability by recognizing and binding to the m6A site. Additionally, METTL3 decreased the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 axis. Furthermore, in vivo studies showed that HCC models with low METTL3/IGF2BP2 expression have higher radiosensitivity. In conclusion, our study suggests that METTL3 regulates the stability of SLC7A11 mRNA in an m6A/IGF2BP2-dependent manner and the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 pathway, both of which require the m6A methyltransferase activity of METTL3. METTL3 or IGF2BP2 may be promising targets for radiotherapy of HCC.https://doi.org/10.1038/s41419-024-07317-x |
| spellingShingle | Chen Zhang Tianpeng Yang Hanbin Chen Xiaofeng Ding Huajian Chen Zhenzhen Liang Yinlong Zhao Shumei Ma Xiaodong Liu METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression Cell Death and Disease |
| title | METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression |
| title_full | METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression |
| title_fullStr | METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression |
| title_full_unstemmed | METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression |
| title_short | METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression |
| title_sort | mettl3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of slc7a11 expression |
| url | https://doi.org/10.1038/s41419-024-07317-x |
| work_keys_str_mv | AT chenzhang mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT tianpengyang mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT hanbinchen mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT xiaofengding mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT huajianchen mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT zhenzhenliang mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT yinlongzhao mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT shumeima mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression AT xiaodongliu mettl3inhibitionpromotesradiosensitivityinhepatocellularcarcinomathroughregulationofslc7a11expression |