期刊
BLOOD
卷 137, 期 11, 页码 1478-1490出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005199
关键词
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类别
资金
- National Natural Science Foundation of China [81970194, 81770154, 81320108023, 81800205, 81770215, 81730003]
- Guangzhou Municipal Science and Technology Project [202002030059]
- National Science and Technology Major Project [2017ZX09304021]
- National Key R&D Program of China [2019YFC0840604]
- Key R&D Program of Jiangsu Province [BE2019798]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Guangzhou Science Technology and Innovation Commission Technology Research Projects [201805010005]
The study reveals that the Otub1/c-Maf axis could be a potential therapeutic target for multiple myeloma, with Otub1 preventing c-Maf degradation and enhancing its transcriptional activity, and LanC inhibiting c-Maf deubiquitination and inducing its degradation to suppress MM growth and prolong overall survival.
The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the present study, we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination, thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N terminus but is independent of UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf recognition element-driven luciferase-based screen against US Food and Drug Administration-approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf deubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice, but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.
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