HDAC inhibition induces CD26 expression on myeloma cells via the c-Myc/Sp1-mediated promoter activation.

CD26 is ubiquitously and intensely expressed in osteoclasts in multiple myeloma (MM) patients, whereas its expression in plasma cells of MM patients is heterogeneous because of its cellular diversity, immune escape and disease progression. Decreased expression levels of CD26 in myeloma cells constitutes one of the mechanisms underlying resistance to humanized anti-CD26 monoclonal antibody (mAb) therapy in MM. In the present study, we show that histone deacetylase inhibition (HDACi) with broad or class-specific inhibitors involves the induction of CD26 expression on CD26neg myeloma cells both transcriptionally and translationally. Furthermore, DPPⅣenzymatic activity was concomitantly enhanced in myeloma cells. Combined treatment with HDACi plus CD26mAb synergistically facilitated lysis of CD26neg myeloma cells not only by antibody-dependent cellular cytotoxicity (ADCC) but also by the direct effects of mAb. Of note, its combination readily augmented lysis of CD26neg cell populations, refractory to CD26mAb or HDACi alone. Chromatin immunoprecipitation assay revealed that HDACi increased acetylation of histone 3 lysine 27 at the CD26 promoter of myeloma cells. Moreover, in the absence of HDACi, c-Myc was attached to the CD26 promoter via Sp1 on the proximal G-C box of myeloma cells, whereas, in the presence of HDACi, c-Myc was detached from Sp1 with increased acetylation of c-Myc on the promoter, leading to activation of the CD26 promoter and initiation of transcription in myeloma cells. Collectively, these results confirm that HDACi plays crucial roles not only through its anti-myeloma activity but by sensitizing CD26neg myeloma cells to CD26mAb via c-Myc/Sp1-mediated CD26 induction, thereby augmenting its cytotoxicity.