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

Ke Li, Feng Wang, Zhao-na Yang, Ting-ting Zhang, Yu-fen Yuan, Chen-xi Zhao, Zaiwuli Yeerjiang, Bing Cui, Fang Hua, Xiao-xi Lv, Xiao-wei Zhang, Jiao-jiao Yu, Shan-shan Liu, Jin-mei Yu, Shuang Shang, Yang Xiao and Zhuo-wei Hu ()
Additional contact information
Ke Li: Central South University
Feng Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Zhao-na Yang: Chinese Academy of Medical Sciences & Peking Union Medical College
Ting-ting Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College
Yu-fen Yuan: Henan University of Science and Technology
Chen-xi Zhao: Chinese Academy of Medical Sciences & Peking Union Medical College
Zaiwuli Yeerjiang: Chinese Academy of Medical Sciences & Peking Union Medical College
Bing Cui: Chinese Academy of Medical Sciences & Peking Union Medical College
Fang Hua: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiao-xi Lv: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiao-wei Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College
Jiao-jiao Yu: Chinese Academy of Medical Sciences & Peking Union Medical College
Shan-shan Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Jin-mei Yu: Chinese Academy of Medical Sciences & Peking Union Medical College
Shuang Shang: Chinese Academy of Medical Sciences & Peking Union Medical College
Yang Xiao: Central South University
Zhuo-wei Hu: Central South University

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-20107-1

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