E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC
Summary: Targeting lysine-specific histone demethylase 1A (LSD1) can improve tumor immunogenicity of poorly immunogenic tumors, such as non-small cell lung cancer (NSCLC), with elevated T cell infiltration and sensitize tumors to anti-PD-1 therapy. However, the lack of reliable biomarkers limits uti...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723014894 |
| _version_ | 1797598005598093312 |
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| author | Feiyu Tang Can Lu Xiang He Wei Lin Bowen Xie Xing Gao Yang Peng Desong Yang Lunquan Sun Liang Weng |
| author_facet | Feiyu Tang Can Lu Xiang He Wei Lin Bowen Xie Xing Gao Yang Peng Desong Yang Lunquan Sun Liang Weng |
| author_sort | Feiyu Tang |
| collection | DOAJ |
| description | Summary: Targeting lysine-specific histone demethylase 1A (LSD1) can improve tumor immunogenicity of poorly immunogenic tumors, such as non-small cell lung cancer (NSCLC), with elevated T cell infiltration and sensitize tumors to anti-PD-1 therapy. However, the lack of reliable biomarkers limits utilization of LSD1 inhibitors in cancer therapy. Here, we identify an E3 ligase, Trim35, as an effective biomarker for high activity of LSD1 to predict prognosis of LSD1-targeted therapy as well as immunotherapy. Mechanistically, Trim35 represses LSD1 demethylase activity by mediating K63 ubiquitination at lysine site 422 of LSD1. Suppressed LSD1 activity facilitates ERGIC1 transcription, followed by autophagy inhibition and IFNGR1 stabilization to activate IFN-γ signaling, leading to increased MHC class I expression and immune surveillance of NSCLC cells. Furthermore, combinational use of an LSD1 inhibitor and anti-PD-1 therapy can significantly eradicate poorly immunogenic lung cancer with low Trim35. These findings strongly suggest that Trim35 is a promising biomarker for prediction of immunotherapy outcome in NSCLC. |
| first_indexed | 2024-03-11T03:13:17Z |
| format | Article |
| id | doaj.art-3fa3037225f94209a85ce82084d42f3f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-11T03:13:17Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-3fa3037225f94209a85ce82084d42f3f2023-11-18T04:28:35ZengElsevierCell Reports2211-12472023-12-014212113477E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLCFeiyu Tang0Can Lu1Xiang He2Wei Lin3Bowen Xie4Xing Gao5Yang Peng6Desong Yang7Lunquan Sun8Liang Weng9Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China; Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha 410008, ChinaDepartment of Pathology, Xiangya Hospital, Central South University, Changsha 410008, ChinaXiangya Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, ChinaDepartment of Pathology, Xiangya Hospital, Central South University, Changsha 410008, ChinaInstitute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, ChinaKey Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Department of Stomatology, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Gynecology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, ChinaHunan Clinical Medical Research Center of Accurate Diagnosis and Treatment for Esophageal Carcinoma, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, ChinaXiangya Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China; Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha 410008, China; Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha 410008, China; Corresponding authorXiangya Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China; Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha 410008, China; Hunan Provincial Clinical Research Center for Respiratory Diseases, Changsha, China; Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha 410008, China; Corresponding authorSummary: Targeting lysine-specific histone demethylase 1A (LSD1) can improve tumor immunogenicity of poorly immunogenic tumors, such as non-small cell lung cancer (NSCLC), with elevated T cell infiltration and sensitize tumors to anti-PD-1 therapy. However, the lack of reliable biomarkers limits utilization of LSD1 inhibitors in cancer therapy. Here, we identify an E3 ligase, Trim35, as an effective biomarker for high activity of LSD1 to predict prognosis of LSD1-targeted therapy as well as immunotherapy. Mechanistically, Trim35 represses LSD1 demethylase activity by mediating K63 ubiquitination at lysine site 422 of LSD1. Suppressed LSD1 activity facilitates ERGIC1 transcription, followed by autophagy inhibition and IFNGR1 stabilization to activate IFN-γ signaling, leading to increased MHC class I expression and immune surveillance of NSCLC cells. Furthermore, combinational use of an LSD1 inhibitor and anti-PD-1 therapy can significantly eradicate poorly immunogenic lung cancer with low Trim35. These findings strongly suggest that Trim35 is a promising biomarker for prediction of immunotherapy outcome in NSCLC.http://www.sciencedirect.com/science/article/pii/S2211124723014894CP: CancerCP: Immunology |
| spellingShingle | Feiyu Tang Can Lu Xiang He Wei Lin Bowen Xie Xing Gao Yang Peng Desong Yang Lunquan Sun Liang Weng E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC Cell Reports CP: Cancer CP: Immunology |
| title | E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC |
| title_full | E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC |
| title_fullStr | E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC |
| title_full_unstemmed | E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC |
| title_short | E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC |
| title_sort | e3 ligase trim35 inhibits lsd1 demethylase activity through k63 linked ubiquitination and enhances anti tumor immunity in nsclc |
| topic | CP: Cancer CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723014894 |
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