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

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 Otub1/c-Maf axis could be a potential target. Otub1, OTU family deubiquitinase, was interact with by mass spectrometry. Otub1 abrogates K48-linked polyubiquitination, thus preventing its degradation and enhancing transcriptional activity. Specifically, this deubiquitinating activity depends on Lys71 N terminus independent of UBE2O, known E2 c-Maf. promotes MM cell survival tumor growth. contrast, silence leads c-Maf-expressing apoptosis. Therefore, MM. order explore concept, performed recognition element–driven luciferase-based screen against US Food Drug Administration–approved drugs natural products, from which generic cardiac glycoside lanatoside C (LanC) prevent deubiquitination induces disrupting interaction Consequently, LanC inhibits activity, apoptosis, suppresses growth prolongs overall model mice, without apparent toxicity. study identifies novel deubiquitinase establishes that