Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer
Abstract In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that co...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05869-y |
| _version_ | 1827928421031739392 |
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| author | Xiaochao Wang Yan Hao Jianfeng Chen Peipei Ding Xinyue Lv Danlei Zhou Ling Li Luying Li Yanqing Xu Yumeng Zhu Wei Zhang Lu Chen Tian Liao Xianghuo He Qing-Hai Ji Weiguo Hu |
| author_facet | Xiaochao Wang Yan Hao Jianfeng Chen Peipei Ding Xinyue Lv Danlei Zhou Ling Li Luying Li Yanqing Xu Yumeng Zhu Wei Zhang Lu Chen Tian Liao Xianghuo He Qing-Hai Ji Weiguo Hu |
| author_sort | Xiaochao Wang |
| collection | DOAJ |
| description | Abstract In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance. |
| first_indexed | 2024-03-13T06:08:27Z |
| format | Article |
| id | doaj.art-71b27402e9c24bd4ab81a605d8232ff4 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-13T06:08:27Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-71b27402e9c24bd4ab81a605d8232ff42023-06-11T11:26:46ZengNature Publishing GroupCell Death and Disease2041-48892023-06-0114611310.1038/s41419-023-05869-yNuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancerXiaochao Wang0Yan Hao1Jianfeng Chen2Peipei Ding3Xinyue Lv4Danlei Zhou5Ling Li6Luying Li7Yanqing Xu8Yumeng Zhu9Wei Zhang10Lu Chen11Tian Liao12Xianghuo He13Qing-Hai Ji14Weiguo Hu15Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan UniversityFudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan UniversityAbstract In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.https://doi.org/10.1038/s41419-023-05869-y |
| spellingShingle | Xiaochao Wang Yan Hao Jianfeng Chen Peipei Ding Xinyue Lv Danlei Zhou Ling Li Luying Li Yanqing Xu Yumeng Zhu Wei Zhang Lu Chen Tian Liao Xianghuo He Qing-Hai Ji Weiguo Hu Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer Cell Death and Disease |
| title | Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer |
| title_full | Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer |
| title_fullStr | Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer |
| title_full_unstemmed | Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer |
| title_short | Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer |
| title_sort | nuclear complement c3b promotes paclitaxel resistance by assembling the sin3a hdac1 2 complex in non small cell lung cancer |
| url | https://doi.org/10.1038/s41419-023-05869-y |
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