TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33298911.
- Also identified by DOI 10.1038/s41467-020-20107-1 and PMC identifier 7725785.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 Myc<sup>Eμ</sup> 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.
Medical subject headings
- Cell Cycle Proteins
- Lymphoma, Non-Hodgkin
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins c-myc
- Repressor Proteins
- Ubiquitin-Protein Ligases