E3 ligase Trim35 inhibits LSD1 demethylase activity through K63-linked ubiquitination and enhances anti-tumor immunity in NSCLC
Feiyu Tang,
Can Lu,
Xiang He,
Wei Lin,
Bowen Xie,
Xing Gao,
Yang Peng,
Desong Yang,
Lunquan Sun,
Liang Weng
Affiliations
Feiyu Tang
Xiangya 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
Can Lu
Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
Xiang He
Xiangya 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
Wei Lin
Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China
Bowen Xie
Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
Xing Gao
Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Department of Stomatology, Xiangya Hospital, Central South University, Changsha 410008, China
Yang Peng
Department of Gynecology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
Desong Yang
Hunan 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, China
Lunquan Sun
Xiangya 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 author
Liang Weng
Xiangya 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 author
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.
