TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation.
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 MycE? 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.
Mesh Terms:
Adolescent, Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Cell Cycle Proteins, Cell Line, Tumor, Cell Self Renewal, Chromatin Immunoprecipitation Sequencing, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Gene Knock-In Techniques, Gene Knockdown Techniques, HEK293 Cells, Humans, Lymphoma, Non-Hodgkin, Male, Mice, Mice, Knockout, Middle Aged, Primary Cell Culture, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein-Serine-Threonine Kinases, Proteolysis, Proto-Oncogene Proteins c-myc, RNA-Seq, Repressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination, Xenograft Model Antitumor Assays, Young Adult
Adolescent, Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Agents, Cell Cycle Proteins, Cell Line, Tumor, Cell Self Renewal, Chromatin Immunoprecipitation Sequencing, Disease Progression, Female, Gene Expression Regulation, Neoplastic, Gene Knock-In Techniques, Gene Knockdown Techniques, HEK293 Cells, Humans, Lymphoma, Non-Hodgkin, Male, Mice, Mice, Knockout, Middle Aged, Primary Cell Culture, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein-Serine-Threonine Kinases, Proteolysis, Proto-Oncogene Proteins c-myc, RNA-Seq, Repressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination, Xenograft Model Antitumor Assays, Young Adult
Nat Commun
Date: Dec. 09, 2019
PubMed ID: 33298911
View in: Pubmed Google Scholar
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