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dc.contributor.authorToloczko, Aleksandra
dc.contributor.authorGuo, Fusheng
dc.contributor.authorYuen, Hiu-Fung
dc.contributor.authorWen, Qing
dc.contributor.authorWood, Stephen A
dc.contributor.authorOng, Yan Shan
dc.contributor.authorChan, Pei Yi
dc.contributor.authorShaik, Asfa Alli
dc.contributor.authorGunaratne, Jayantha
dc.contributor.authorDunne, Mark J
dc.contributor.authorHong, Wanjin
dc.contributor.authorChan, Siew Wee
dc.date.accessioned2018-01-03T22:39:39Z
dc.date.available2018-01-03T22:39:39Z
dc.date.issued2017
dc.identifier.issn0008-5472
dc.identifier.doi10.1158/0008-5472.CAN-16-3413
dc.identifier.urihttp://hdl.handle.net/10072/356292
dc.description.abstractThe core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research
dc.relation.ispartofpagefrom4921
dc.relation.ispartofpageto4933
dc.relation.ispartofissue18
dc.relation.ispartofjournalCancer Research
dc.relation.ispartofvolume77
dc.subject.fieldofresearchOncology and Carcinogenesis not elsewhere classified
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode111299
dc.subject.fieldofresearchcode1112
dc.titleDeubiquitinating enzyme USP9X suppresses tumor growth via LATS kinase and core components of the Hippo pathway
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorWood, Stephen A.


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