National Clinical Research Center for Metabolic Disease, Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, 410011, Changsha, Hunan, China.
NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050, Beijing, China.
Nat Commun. 2020 Dec 9;11(1):6316. doi: 10.1038/s41467-020-20107-1.
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 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.
转录因子 MYC 在几乎所有人类癌症中失调，特别是在侵袭性淋巴瘤中，通过染色体易位、扩增和转录过度激活。在这里，我们报告三结构域蛋白 3（TRIB3）的高表达与淋巴瘤标本中 MYC 表达的升高呈正相关；TRIB3 缺失通过降低 MYC 表达来减弱 MYC 驱动的淋巴瘤的起始和进展。在机制上，TRIB3 与 MYC 相互作用，抑制 E3 泛素连接酶 UBE3B 介导的 MYC 泛素化和降解，从而增强 MYC 的转录活性，导致淋巴瘤细胞的高增殖和自我更新。使用一种肽来干扰 TRIB3-MYC 相互作用，加上阿霉素，可减少 Myc 小鼠和患者来源的异种移植中的肿瘤负担。UBE3B、TRIB3 和 MYC 的病理生理相关性在人类淋巴瘤中得到进一步证实。我们的研究强调了控制 MYC 表达的关键机制，并为治疗高 TRIB3-MYC 表达的淋巴瘤提供了一种潜在的治疗选择。
