Kamran M, Long Z-J, Xu D, Lv S-S, Liu B, Wang C-L, Xu J, Lam E W-F, Liu Q
Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian/State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
Department of Hematology, The Third Affiliated Hospital; Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
Oncogenesis. 2017 Feb 20;6(2):e298. doi: 10.1038/oncsis.2016.80.
Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies. However, little is known about its role in gastric cancer prognosis and genotoxic resistance. Here we found that AURKA was highly overexpressed in gastric cancer and inversely correlated with disease prognosis. Overexpression of AURKA exacerbated gastric cancer drug resistance through upregulating the expression of the anti-apoptotic protein Survivin. Conversely, we demonstrated that AURKA depletion caused a decrease in Survivin protein levels by increasing its ubiquitylation and degradation. Mass spectrometric analysis revealed that upon AURKA depletion, Survivin bound to the FBXL7 E3 ubiquitin ligase, which induced ubiquitin-proteasome degradation of Survivin. In addition, we showed that AURKA regulated FBXL7 both at the levels of transcription and translation. Moreover, proteomic analysis of nuclear AURKA-interacting proteins identified Forkhead box protein P1 (FOXP1). We next showed that AURKA was required for FBXL7 transcription and that AURKA negatively regulated FOXP1-mediated FBXL7 expression. The physiological relevance of the regulation of Survivin by AURKA through the FOXP1-FBXL7 axis was further underscored by the significant positive correlations between AURKA and Survivin expression in gastric cancer patient samples. Moreover, the AURKA depletion or kinase inhibition-induced apoptotic cell death could be reversed by Survivin ectopic overexpression, further supporting that AURKA regulated Survivin to enhance drug resistance. In agreement, inhibition of AURKA synergistically enhanced the cytotoxic effect of DNA-damaging agents in cancer cells by suppressing Survivin expression. Taken together, our data suggest that AURKA restricts Survivin ubiquitylation and degradation in gastric cancer to promote drug resistance and hence the AURKA-Survivin axis can be targeted to promote the efficacy of DNA-damaging agents in gastric cancer.
极光激酶A（AURKA）参与调控细胞周期进程、有丝分裂以及多种恶性肿瘤中一些关键的致癌信号通路。然而，其在胃癌预后和基因毒性抗性中的作用却鲜为人知。在此，我们发现AURKA在胃癌中高度过表达，且与疾病预后呈负相关。AURKA的过表达通过上调抗凋亡蛋白Survivin的表达加剧了胃癌耐药性。相反，我们证明AURKA的缺失通过增加Survivin的泛素化和降解导致其蛋白水平降低。质谱分析显示，AURKA缺失后，Survivin与FBXL7 E3泛素连接酶结合，后者诱导Survivin的泛素 - 蛋白酶体降解。此外，我们表明AURKA在转录和翻译水平上均调控FBXL7。而且，对细胞核中与AURKA相互作用蛋白的蛋白质组学分析鉴定出叉头框蛋白P1（FOXP1）。接下来我们表明AURKA是FBXL7转录所必需的，并且AURKA负向调控FOXP1介导的FBXL7表达。胃癌患者样本中AURKA与Survivin表达之间的显著正相关进一步强调了AURKA通过FOXP1 - FBXL7轴调控Survivin的生理相关性。此外，Survivin的异位过表达可逆转AURKA缺失或激酶抑制诱导的凋亡细胞死亡，进一步支持AURKA通过调控Survivin来增强耐药性。与此一致，抑制AURKA通过抑制Survivin表达协同增强了DNA损伤剂对癌细胞的细胞毒性作用。综上所述，我们的数据表明AURKA在胃癌中限制Survivin的泛素化和降解以促进耐药性，因此AURKA - Survivin轴可作为靶点来提高DNA损伤剂在胃癌中的疗效。
