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Aurora kinase A regulates Survivin stability through targeting FBXL7 in gastric cancer drug resistance and prognosis

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Title: Aurora kinase A regulates Survivin stability through targeting FBXL7 in gastric cancer drug resistance and prognosis
Authors: Kamran, M
Long, Z-J
Xu, D
Lv, S-S
Liu, B
Wang, C-L
Xu, J
Lam, EW
Liu, Q
Item Type: Journal Article
Abstract: 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.
Issue Date: 20-Feb-2017
Date of Acceptance: 7-Nov-2016
URI: http://hdl.handle.net/10044/1/42369
DOI: https://dx.doi.org/10.1038/oncsis.2016.80
ISSN: 2157-9024
Publisher: Nature Publishing Group
Journal / Book Title: Oncogenesis
Volume: 6
Copyright Statement: © The Author(s) 2017. ncogenesis is an open-access journal published by Nature Publishing Group . This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Campaign and Breakthrough Breast Cancer
Funder's Grant Number: C37/A12011
2012NovemberPhD016
2012MayPR070
Publication Status: Published
Article Number: e298
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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