HDAC Inhibition Induces CD26 Expression on Multiple Myeloma Cells via the c-Myc/Sp1-mediated Promoter Activation

CD26 is ubiquitously and intensely expressed in osteoclasts in patients with multiple myeloma, whereas its expression in plasma cells of patients with multiple myeloma is heterogeneous because of its cellular diversity, immune escape, and disease progression. Decreased expression levels of CD26 in myeloma cells constitute one of the mechanisms underlying resistance to humanized anti-CD26 mAb therapy in multiple myeloma. In the current study, we show that histone deacetylase inhibition (HDACi) with broad or class-specific inhibitors involves the induction of CD26 expression on CD26(neg) myeloma cells both transcriptionally and translationally. Furthermore, dipeptidyl peptidase.(DPP.) enzymatic activity was concomitantly enhanced in myeloma cells. Combined treatment with HDACi plus CD26mAb synergistically facilitated lysis of CD26(neg) myeloma cells not only by antibody-dependent cellular cytotoxicity but also by the direct effects ofmAb. Of note, its combination readily augmented lysis of CD26(neg) 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 ofmyeloma cells. Moreover, in the absence of HDACi, c-Myc was attached to the CD26 promoter via Sp1 on the proximalG-C box ofmyeloma cells, whereas, in the presence ofHDACi, c-Myc was detached from Sp1 with increased acetylation of c-Myc on the promoter, leading to activation of theCD26 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 CD26(neg) myeloma cells to CD26mAb via c-Myc/Sp1-mediated CD26 induction, thereby augmenting its cytotoxicity.