HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma
Abstract Protein acetylation modification plays important roles in various aspects of tumor progression. Ferroptosis driven by lethal lipid peroxidation is closely related to tumor development. Targeting ferroptosis has become a promising strategy. However, the crosstalk between protein acetylation...
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| Format: | Article |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07477-4 |
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| author | Peijun Zhou Xingzhi Peng Kun zhang Jin Cheng Min Tang Lin Shen Qin Zhou Dan Li Lifang Yang |
| author_facet | Peijun Zhou Xingzhi Peng Kun zhang Jin Cheng Min Tang Lin Shen Qin Zhou Dan Li Lifang Yang |
| author_sort | Peijun Zhou |
| collection | DOAJ |
| description | Abstract Protein acetylation modification plays important roles in various aspects of tumor progression. Ferroptosis driven by lethal lipid peroxidation is closely related to tumor development. Targeting ferroptosis has become a promising strategy. However, the crosstalk between protein acetylation and ferroptosis remains unclear. In present study, we found that the acetylation of acyl-CoA synthase long-chain family member 4 (ACSL4) enhances its protein stability and a double-edged sword regulation in nasopharyngeal carcinoma (NPC). On the one hand, ACSL4 could promote the malignant progress of tumors; on the other hand, it enhanced radiosensitivity by endowing NPC cells with ferroptosis-sensitive properties in vitro and in vivo. Mechanistically, histone acetyltransferase 1 (HAT1) directly promotes the acetylation of ACSL4 at lysine 383, and deacetylase sirtuin 3 (SIRT3) mediates the deacetylation of ACSL4. Meanwhile, another deacetylase histone deacetylase 2 (HDAC2) enhances ACSL4 acetylation through inhibiting the transcription of SIRT3. Acetylation of ACSL4 inhibits F-box protein 10 (FBXO10)-mediated K48-linked ubiquitination, resulting in enhanced protein stability of ACSL4. This study reveals the novel regulatory mechanism of ferroptosis-related protein from the perspective of protein acetylation, and provides a novel method for the radiosensitivity of NPC. |
| format | Article |
| id | doaj-art-ddbdec692e80439da9c549ffd49652fc |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-ddbdec692e80439da9c549ffd49652fc2025-08-20T03:05:44ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111810.1038/s41419-025-07477-4HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinomaPeijun Zhou0Xingzhi Peng1Kun zhang2Jin Cheng3Min Tang4Lin Shen5Qin Zhou6Dan Li7Lifang Yang8Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityCancer Research Institute, School of Basic Medicine Science, Central South UniversityDepartment of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityDepartment of Life Science, College of Biology, Hunan UniversityDepartment of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityAbstract Protein acetylation modification plays important roles in various aspects of tumor progression. Ferroptosis driven by lethal lipid peroxidation is closely related to tumor development. Targeting ferroptosis has become a promising strategy. However, the crosstalk between protein acetylation and ferroptosis remains unclear. In present study, we found that the acetylation of acyl-CoA synthase long-chain family member 4 (ACSL4) enhances its protein stability and a double-edged sword regulation in nasopharyngeal carcinoma (NPC). On the one hand, ACSL4 could promote the malignant progress of tumors; on the other hand, it enhanced radiosensitivity by endowing NPC cells with ferroptosis-sensitive properties in vitro and in vivo. Mechanistically, histone acetyltransferase 1 (HAT1) directly promotes the acetylation of ACSL4 at lysine 383, and deacetylase sirtuin 3 (SIRT3) mediates the deacetylation of ACSL4. Meanwhile, another deacetylase histone deacetylase 2 (HDAC2) enhances ACSL4 acetylation through inhibiting the transcription of SIRT3. Acetylation of ACSL4 inhibits F-box protein 10 (FBXO10)-mediated K48-linked ubiquitination, resulting in enhanced protein stability of ACSL4. This study reveals the novel regulatory mechanism of ferroptosis-related protein from the perspective of protein acetylation, and provides a novel method for the radiosensitivity of NPC.https://doi.org/10.1038/s41419-025-07477-4 |
| spellingShingle | Peijun Zhou Xingzhi Peng Kun zhang Jin Cheng Min Tang Lin Shen Qin Zhou Dan Li Lifang Yang HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma Cell Death and Disease |
| title | HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma |
| title_full | HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma |
| title_fullStr | HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma |
| title_full_unstemmed | HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma |
| title_short | HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma |
| title_sort | hat1 hdac2 mediated acsl4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma |
| url | https://doi.org/10.1038/s41419-025-07477-4 |
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