TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation

Ke Li,Shuang Shang,Xiao-Wei Zhang,Fang Hua,Zhao-Na Yang,Yu-Fen Yuan,Zaiwuli Yeerjiang,Chen-Xi Zhao,Feng Wang,Bing Cui,Ting-Ting Zhang,Jiao-Jiao Yu,Shan-Shan Liu,Zhuo-Wei Hu,Yang Xiao,Xiao-Xi Lv,Jin-Mei Yu

doi:10.1038/s41467-020-20107-1

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.

Highlights

The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation
We found that tribbles homologue 3 (TRIB3) interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which causes high proliferation and self-renewal of lymphoma cells
To examine the role of TRIB3 in lymphomagenesis, we searched the Oncomine database and found that TRIB3 expression was elevated in peripheral T-cell lymphoma (PTCL) and diffuse large Bcell lymphoma (DLBCL) compared to normal lymphocytes (Fig. 1a, b)

Summary

Introduction

The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. 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. Targeting MYC, especially in combination with traditional therapies, is considered an attractive therapeutic strategy for lymphomas and other MYC-driven cancers. Despite its attractiveness as a cancer target, MYC has been considered “undruggable” and remains outside reach of pharmacological regulation, mainly due to its nuclear localization, lack of a defined ligand-binding site, and large protein-protein interaction (PPI) surface[26,27]. We found that TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which causes high proliferation and self-renewal of lymphoma cells. This study reveals several functional implications for MYC-associated lymphoma therapy

Methods

Results

Conclusion