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

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.