Suppression of DLBCL Progression by the E3 Ligase Trim35 Is Mediated by CLOCK Degradation and NK Cell Infiltration

• Published in: Journal of Immunology Research Vol. 2021; pp. 9995869 - 13
• Main Authors: Tan, Xiyan, Cao, Fuyang, Tang, Feiyu, Lu, Can, Yu, Qiaoyan, Feng, Songshan, Yang, Zhanghuan, Chen, Songming, He, Xiang, He, Jiang, Weng, Liang, Sun, Lunquan
• Format: Journal Article
• Language: English
• Published: Egypt Hindawi 2021; John Wiley & Sons, Inc; Hindawi Limited
• Subjects: Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; B-cell lymphoma; Biomarkers, Tumor - metabolism; Cancer; Carcinogenesis; Cell cycle; Cell Line, Tumor; Cell Movement - genetics; Cell proliferation; Chemotherapy; Circadian Clocks - genetics; Circadian rhythm; Circadian rhythms; CLOCK Proteins - metabolism; CRISPR; Cyclophosphamide; Degradation; Disease Progression; Doxorubicin; Female; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Immunology; Infiltration; Killer cells; Killer Cells, Natural - immunology; Ligases; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - diagnosis; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - mortality; Male; Medical prognosis; Medical research; Medicine, Experimental; Metastases; Microenvironments; Middle Aged; Natural killer cells; Non-Hodgkin's lymphomas; Prednisone; Proteins; Proteolysis; Survival Analysis; Tumor Microenvironment; Type 2 diabetes; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Vincristine; China
• ISSN: 2314-8861; 2314-7156
• DOI: 10.1155/2021/9995869

The majority of diffuse large B-cell lymphoma (DLBCL) patients develop relapsed or refractory disease after standard ruxolitinib, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, which is partly related to a dysregulated tumor immune microenvironment. However, how the infiltration of immune cells is appropriately regulated is poorly understood. Herein, we show that the E3 ubiquitin ligase Trim35 is expressed at low levels in human DLBCL tissues. We also show that overexpression of Trim35 suppresses DLBCL cell proliferation and correlates with inferior survival in DLBCL patients. Our mechanistic study shows that Trim35 functions as an E3 ligase to mediate the ubiquitination and degradation of CLOCK, a key regulator of circadian rhythmicity. High expression of Trim35 correlates with NK cell infiltration in DLBCL, partly due to the degradation of CLOCK. Consistently, patients with high expression of CLOCK show poor overall survival. Overall, these findings suggest that Trim35 suppresses the progression of DLBCL by modulating the tumor immune microenvironment, indicating that it may be a promising diagnostic and prognostic biomarker in DLBCL.