EPS8-mediated regulation of multiple myeloma cell growth and survival

Epidermal growth factor receptor pathway substrate 8 (EPS8), which acts as an oncoprotein in various carcinomas, is associated with tumor progression. However, its impact on multiple myeloma (MM) has not been determined. Here, we investigate the role of EPS8 in MM and consider the potential of EPS8 as an anti-MM target. We confirmed overexpression of EPS8 in MM cells compared with plasma cells derived from healthy volunteers. Knockdown of EPS8 significantly abrogated MM cell survival, migration and invasion. Moreover, depletion of EPS8 overcomes drug resistance. TNFα or bone marrow stromal cell culture supernatants induce EPS8, which is blocked by the IKKβ inhibitor MLN120B, suggesting that EPS8 is regulated by NF-κB signaling in MM cells. Mithramycin (MTM), a selective EPS8 inhibitor, suppressed MM cell proliferation and exerted potent anti-MM activity in xenograft tumor models. A synergistic effect of MTM and bortezomib (BTZ) was also observed in vitro and in vivo. Mechanistically, treatment of MM cells with MTM reduced the expression of EPS8 and related pathways. Additionally, the EPS8-knockdown phenotype can be rescued by shRNA-resistant EPS8. Taken together, we describe overexpression of EPS8 in MM by highlighting its role as a potential target and reveal therapeutic targeting of EPS8 by MTM as a novel therapy for MM.