1. TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation
- Author
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Fang Hua, Bing Cui, Yu-fen Yuan, Yang Xiao, Zaiwuli Yeerjiang, Chen-xi Zhao, Xiaowei Zhang, Ting-ting Zhang, Xiaoxi Lv, Jiao-jiao Yu, Zhao-na Yang, Shan-Shan Liu, Feng Wang, Zhuo-Wei Hu, Ke Li, Shuang Shang, and Jin-mei Yu
- Subjects
Male ,0301 basic medicine ,Ubiquitylation ,General Physics and Astronomy ,Cell Cycle Proteins ,Mice ,0302 clinical medicine ,Ubiquitin ,Transcription (biology) ,hemic and lymphatic diseases ,Gene Knock-In Techniques ,RNA-Seq ,Cell Self Renewal ,Aged, 80 and over ,Mice, Knockout ,Regulation of gene expression ,Non-hodgkin lymphoma ,Multidisciplinary ,biology ,Lymphoma, Non-Hodgkin ,Middle Aged ,Ubiquitin ligase ,Gene Expression Regulation, Neoplastic ,TRIB3 ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Disease Progression ,Chromatin Immunoprecipitation Sequencing ,Female ,Proteasome Inhibitors ,Adult ,Proteasome Endopeptidase Complex ,Adolescent ,Ubiquitin-Protein Ligases ,Science ,Primary Cell Culture ,Antineoplastic Agents ,Protein Serine-Threonine Kinases ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proto-Oncogene Proteins c-myc ,Young Adult ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Transcription factor ,Aged ,HEK 293 cells ,Ubiquitination ,General Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,Lymphoma ,Repressor Proteins ,HEK293 Cells ,030104 developmental biology ,Proteolysis ,biology.protein ,Cancer research - Abstract
The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in MycEμ mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression., c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.
- Published
- 2020