Targeting CD26 suppresses proliferation of malignant mesothelioma cell via downmodulation of ubiquitin-specific protease 22

Malignant pleural mesothelioma (MPM) is an aggressive malignancy arising from mesothelial lining of pleura. It is associated with a poor prognosis, partly due to the lack of a precise understanding of the molecular mechanisms associated with its malignant behavior. In the present study, we expanded on our previous studies on cell cycle control of MPM cells by targeting CD26 molecule with humanized anti-CD26 monoclonal antibody (HuCD26mAb), focusing particularly on ubiquitin-specific protease 22 (USP22). We showed that USP22 protein expression is detected in clinical specimens of MPM and that USP22 knockdown, as well as CD26 knockdown, significantly inhibits the growth and proliferation of MPM cells in vitro and in vivo. Moreover, depletion of both USP22 and CD26 suppresses MPM cell proliferation even more profoundly. Furthermore, expression levels of USP22 correlate with those of CD26. HuCD26mAb treatment induces a decrease in USP22 level through its interaction with the CD26 molecule, leading to increased levels of ubiquitinated histone H2A and p21. By demonstrating a CD26-related linkage with USP22 in MPM cell inhibition induced by HuCD26mAb, our present study hence characterizes USP22 as a novel target molecule while concurrently suggesting a new therapeutic strategy for MPM.