دورية أكاديمية
Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.
| العنوان: | Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. |
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| المؤلفون: | Bian Y; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Li W; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Kremer DM; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA., Sajjakulnukit P; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA., Li S; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA., Crespo J; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Nwosu ZC; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA., Zhang L; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA., Czerwonka A; Department of Virology and Immunology, Maria Curie-Skłodowska University, Lublin, Poland., Pawłowska A; First Chair and Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland., Xia H; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Li J; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Liao P; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Yu J; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Vatan L; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Szeliga W; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Wei S; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Grove S; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Liu JR; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA., McLean K; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA., Cieslik M; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA., Chinnaiyan AM; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.; Department of Urology, University of Michigan, Ann Arbor, MI, USA.; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA., Zgodziński W; Second Department of General, Gastrointestinal Surgery and Surgical Oncology of the Alimentary Tract, Medical University of Lublin, Lublin, Poland., Wallner G; Second Department of General, Gastrointestinal Surgery and Surgical Oncology of the Alimentary Tract, Medical University of Lublin, Lublin, Poland., Wertel I; First Chair and Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland., Okła K; First Chair and Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland., Kryczek I; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Lyssiotis CA; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA.; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA.; Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA., Zou W; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu.; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu.; Department of Pathology, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu.; Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu.; Graduate Program in Cancer Biology, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu. |
| المصدر: | Nature [Nature] 2020 Sep; Vol. 585 (7824), pp. 277-282. Date of Electronic Publication: 2020 Sep 02. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| مواضيع طبية MeSH: | Methylation*, Amino Acid Transport System L/*metabolism , CD8-Positive T-Lymphocytes/*metabolism , Histones/*metabolism , Methionine/*metabolism , Neoplasms/*metabolism, Amino Acid Transport System L/deficiency ; Animals ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Epigenesis, Genetic ; Female ; Histones/chemistry ; Humans ; Mice ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/pathology ; Receptors, Antigen, T-Cell/metabolism ; STAT5 Transcription Factor/metabolism |
| مستخلص: | Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours 1-4 , but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8 + T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach. |
| التعليقات: | Comment in: Immunol Cell Biol. 2020 Sep;98(8):623-625. (PMID: 32842169) Comment in: Cell Metab. 2020 Nov 3;32(5):699-701. (PMID: 33147482) |
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| معلومات مُعتمدة: | CA099985 United States CA NCI NIH HHS; R01 CA193136 United States CA NCI NIH HHS; P30 CA046592 United States CA NCI NIH HHS; CA217648 United States CA NCI NIH HHS; CA152470 United States CA NCI NIH HHS; R01 CA152470 United States CA NCI NIH HHS; R01 CA123088 United States CA NCI NIH HHS; U24 DK097153 United States DK NIDDK NIH HHS; R37 CA237421 United States CA NCI NIH HHS; R01 CA099985 United States CA NCI NIH HHS; R01 CA217510 United States CA NCI NIH HHS; DK097153 United States NH NIH HHS; R01 CA190176 United States CA NCI NIH HHS; R01 CA214911 United States CA NCI NIH HHS; CA123088 United States CA NCI NIH HHS; CA193136 United States CA NCI NIH HHS; T32 CA009676 United States CA NCI NIH HHS; R01 CA248430 United States CA NCI NIH HHS; R01 CA211016 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Amino Acid Transport System L) 0 (Histones) 0 (Receptors, Antigen, T-Cell) 0 (STAT5 Transcription Factor) 0 (Slc43a2 protein, mouse) AE28F7PNPL (Methionine) |
| تواريخ الأحداث: | Date Created: 20200904 Date Completed: 20200921 Latest Revision: 20220418 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC7486248 |
| DOI: | 10.1038/s41586-020-2682-1 |
| PMID: | 32879489 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1476-4687 |
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| DOI: | 10.1038/s41586-020-2682-1 |