2. Academic Validation
  3. Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma

Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma

  • Blood. 2021 Mar 18;137(11):1478-1490. doi: 10.1182/blood.2020005199.
Yujia Xu 1 2,  Min Xu 3,  Jiefei Tong 4,  Xiaowen Tang 5,  Jinhao Chen 3,  Xuehan Chen 2,  Zubin Zhang 2,  Biyin Cao 2,  A Keith Stewart 6,  Michael F Moran 4,  Depei Wu 5,  Xinliang Mao 1 2 7
Affiliations

Affiliations

  • 1 Guangzhou Institute of Cardiovascular Diseases, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Diseases, The Second Affiliated Hospital-Guangdong Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China.
  • 2 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, People's Republic of China.
  • 3 Department of Hematology, Zhangjiagang Hospital of Soochow University, Zhangjiagang, China.
  • 4 Program in Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 5 National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China.
  • 6 Division of Hematology, Mayo Clinic Scottsdale, AZ; and.
  • 7 Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
PMID: 32842143 DOI: 10.1182/blood.2020005199
Abstract

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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