NEK2 Induces Autophagy‐mediated Bortezomib Resistance by Stabilizing Beclin‐1 in Multiple Myeloma

NEK2 is associated with drug resistance in multiple cancers. Our previous studies indicated that high NEK2 confers inferior survival in multiple myeloma (MM); thus, a better understanding of the mechanisms by which NEK2 induces drug resistance in MM is required. In this study, we discovered that NEK2 enhances MM cell autophagy, and a combination of autophagy inhibitor chloroquine (CQ) and chemotherapeutic bortezomib (BTZ) significantly prevents NEK2-induced drug resistance in MM cells. Interestingly, NEK2 was found to bind and stabilize Beclin-1 protein but did not affect its mRNA expression and phosphorylation. Moreover, autophagy enhanced by NEK2 was significantly prevented by knockdown of Beclin-1 in MM cells, suggesting that Beclin-1 mediates NEK2-induced autophagy. Further studies demonstrated that Beclin-1 ubiquitination is decreased through NEK2 interaction with USP7. Importantly, knockdown of Beclin-1 sensitized NEK2-overexpressing MM cells to BTZ in vitro and in vivo. In conclusion, we identify a novel mechanism whereby autophagy is activated by the complex of NEK2/USP7/Beclin-1 in MM cells. Targeting the autophagy signaling pathway may provide a promising therapeutic strategy to overcome NEK2-induced drug resistance in MM.