NEK2 induces autophagy‐mediated bortezomib resistance by stabilizing Beclin‐1 in multiple myeloma. Issue 4 (29th January 2020)

• Record Type: Journal Article
• Authors: Xia, Jiliang; He, Yanjuan; Meng, Bin; Chen, Shilian; Zhang, Jingyu; Wu, Xuan; Zhu, Yinghong; Shen, Yi; Feng, Xiangling; Guan, Yongjun; Kuang, Chunmei; Guo, Jiaojiao; Lei, Qian; Wu, Yangbowen; An, Gang; Li, Guancheng; Qiu, Lugui; Zhan, Fenghuang; Zhou, Wen
• Is Part Of: Molecular oncology. Volume 14:Issue 4(2020)
• Page Start: 763
• Page End: 778
• Publication Date: 2020-01-29
• Subjects: autophagy -- Beclin‐1 -- multiple myeloma -- NEK2 -- ubiquitination; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12641
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : 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. Abstract : Autophagy is associated with bortezomib resistance in multiple myeloma (MM). Here, we show that NEK2 stabilizes Beclin‐1 through USP7‐mediated deubiquitination, thereby enhancing autophagy and eventually inducing bortezomib resistance in MM cell. Moreover, knockdown of Beclin‐1 profoundly inhibits NEK2‐mediated bortezomib resistance. These findings indicate that NEK2 induces autophagy‐mediated bortezomib resistance through stabilizing Beclin‐1 in MM cell.