Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer
Abstract Tumor metabolism often interferes with the immune microenvironment. Although natural killer (NK) cells play pivotal roles in antitumor immunity, the connection between NK cells and tumor metabolism remains unclear. Our systematic analysis of multiomics data and survival data from colorectal...
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| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02221-y |
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| author | Chen Wei Kun Liao Hao-Jie Chen Zi-Xuan Xiao Qi Meng Ze-Kun Liu Yun-Xin Lu Hui Sheng Hai-Yu Mo Qi-Nian Wu Yi Han Zhao-Lei Zeng Xin-Yuan Guan Hui-Yan Luo Huai-Qiang Ju Rui-Hua Xu |
| author_facet | Chen Wei Kun Liao Hao-Jie Chen Zi-Xuan Xiao Qi Meng Ze-Kun Liu Yun-Xin Lu Hui Sheng Hai-Yu Mo Qi-Nian Wu Yi Han Zhao-Lei Zeng Xin-Yuan Guan Hui-Yan Luo Huai-Qiang Ju Rui-Hua Xu |
| author_sort | Chen Wei |
| collection | DOAJ |
| description | Abstract Tumor metabolism often interferes with the immune microenvironment. Although natural killer (NK) cells play pivotal roles in antitumor immunity, the connection between NK cells and tumor metabolism remains unclear. Our systematic analysis of multiomics data and survival data from colorectal cancer (CRC) patients uncovered a novel association between mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) and NK cell infiltration that influences disease progression. ACAT1, a metabolic enzyme involved in reversible conversion of acetoacetyl-CoA to two molecules of acetyl-CoA, exhibits nuclear protein acetylation activity through its translocation. Under immune stimulation, mitochondrial ACAT1 can be phosphorylated at serine 60 (S60) and enters the nucleus; however, this process is hindered in nutrient-poor tumor microenvironments. Nuclear ACAT1 directly acetylates lysine 146 of p50 (NFKB1), attenuating its DNA binding and transcriptional repression activity and thereby increasing the expression of immune-related factors, which in turn promotes NK cell recruitment and activation to suppress colorectal cancer growth. Furthermore, significant associations are found among low nuclear ACAT1 levels, decreased S60 phosphorylation, and reduced NK cell infiltration, as well as poor prognosis in CRC. Our findings reveal an unexpected function of ACAT1 as a nuclear acetyltransferase and elucidate its role in NK cell-dependent antitumor immunity through p50 acetylation. |
| format | Article |
| id | doaj-art-df350d89b73e40a7be8f4fa1c38cfd3c |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-df350d89b73e40a7be8f4fa1c38cfd3c2025-08-20T03:52:24ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-04-0110111710.1038/s41392-025-02221-yNuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancerChen Wei0Kun Liao1Hao-Jie Chen2Zi-Xuan Xiao3Qi Meng4Ze-Kun Liu5Yun-Xin Lu6Hui Sheng7Hai-Yu Mo8Qi-Nian Wu9Yi Han10Zhao-Lei Zeng11Xin-Yuan Guan12Hui-Yan Luo13Huai-Qiang Ju14Rui-Hua Xu15Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen HospitalDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityAbstract Tumor metabolism often interferes with the immune microenvironment. Although natural killer (NK) cells play pivotal roles in antitumor immunity, the connection between NK cells and tumor metabolism remains unclear. Our systematic analysis of multiomics data and survival data from colorectal cancer (CRC) patients uncovered a novel association between mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) and NK cell infiltration that influences disease progression. ACAT1, a metabolic enzyme involved in reversible conversion of acetoacetyl-CoA to two molecules of acetyl-CoA, exhibits nuclear protein acetylation activity through its translocation. Under immune stimulation, mitochondrial ACAT1 can be phosphorylated at serine 60 (S60) and enters the nucleus; however, this process is hindered in nutrient-poor tumor microenvironments. Nuclear ACAT1 directly acetylates lysine 146 of p50 (NFKB1), attenuating its DNA binding and transcriptional repression activity and thereby increasing the expression of immune-related factors, which in turn promotes NK cell recruitment and activation to suppress colorectal cancer growth. Furthermore, significant associations are found among low nuclear ACAT1 levels, decreased S60 phosphorylation, and reduced NK cell infiltration, as well as poor prognosis in CRC. Our findings reveal an unexpected function of ACAT1 as a nuclear acetyltransferase and elucidate its role in NK cell-dependent antitumor immunity through p50 acetylation.https://doi.org/10.1038/s41392-025-02221-y |
| spellingShingle | Chen Wei Kun Liao Hao-Jie Chen Zi-Xuan Xiao Qi Meng Ze-Kun Liu Yun-Xin Lu Hui Sheng Hai-Yu Mo Qi-Nian Wu Yi Han Zhao-Lei Zeng Xin-Yuan Guan Hui-Yan Luo Huai-Qiang Ju Rui-Hua Xu Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer Signal Transduction and Targeted Therapy |
| title | Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer |
| title_full | Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer |
| title_fullStr | Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer |
| title_full_unstemmed | Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer |
| title_short | Nuclear mitochondrial acetyl-CoA acetyltransferase 1 orchestrates natural killer cell-dependent antitumor immunity in colorectal cancer |
| title_sort | nuclear mitochondrial acetyl coa acetyltransferase 1 orchestrates natural killer cell dependent antitumor immunity in colorectal cancer |
| url | https://doi.org/10.1038/s41392-025-02221-y |
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