CC1007, a small molecular compound, suppresses multiple myeloma via upregulation of Nur77

Abstract

BackgroundMultiple myeloma (MM) is a hematological malignancy of plasma cells characterized by the production of monoclonal immunoglobulin protein. Despite significant advances in the treatment of MM, it remains an incurable disorder owing to its resistance to chemotherapy and refractory nature. Inhibitors of histone deacetylases (HDACIs) have been identified as promising therapeutic drugs for cancer treatment. At present, numerous HDACIs are under study for the treatment of MM in monotherapy or in conjunction with other agents. ObjectivesIn the present study, we investigated the anti-MM effect of CC1007, which was designed to indirectly inhibit class IIa HDACs by binding to myocyte enhancer factor-2 (MEF2) and blocking the targets regulated by the HDAC–MEF2 complex. DesignThe effect of CC1007 on human MM cell lines, namely U266 and MM1.S, and CD138+ cells collected from the bone marrow of patients with MM was evaluated. MethodsThe cells were subjected to growth-inhibition assay, apoptosis assay, cell cycle analysis, real-time PCR, western blotting, immunofluorescence, co-immunoprecipitation, ChIP assay, and siRNA transfection. Statistical differences were compared using two-tailed t tests or one-way analysis of variance followed by the Bonferroni post hoc test. ResultsCC1007 inhibited the proliferation of MM cell lines and primary MM cells and induced their apoptosis and cell cycle arrest. Furthermore, CC1007 decreased the expression of MEF2C and HDAC7, thereby disturbing their interaction and promoting the overexpression of Nur77, a target of MEF2C. The overexpression of Nur77 and its translocation from the nucleus to the cytoplasm resulted in its binding to B-cell lymphoma 2 on the mitochondrial surface, thereby inducing the release of cytochrome C and activating the mitochondrial apoptotic pathway. ConclusionsSince CC1007 demonstrates remarkable anti-MM effect on MM cells, it may be a promising drug for the treatment of MM.