Show simple item record de Barrios O Győrffy, Balázs Fernandez-Acenero MJ Sanchez-Tillo E Sanchez-Moral L Siles L Esteve-Arenys A Roue G Casal JI Darling DS Castells A Postigo A 2017-06-08T07:06:29Z 2017-06-08T07:06:29Z 2017
dc.identifier 85006968681
dc.identifier.citation pagination=666-682; journalVolume=66; journalIssueNumber=4; journalTitle=GUT;
dc.identifier.uri doi:10.1136/gutjnl-2015-310838
dc.description.abstract OBJECTIVE: Understand the role of ZEB1 in the tumour initiation and progression beyond inducing an epithelial-to-mesenchymal transition. DESIGN: Expression of the transcription factor ZEB1 associates with a worse prognosis in most cancers, including colorectal carcinomas (CRCs). The study uses survival analysis, in vivo mouse transgenic and xenograft models, gene expression arrays, immunostaining and gene and protein regulation assays. RESULTS: The poorer survival determined by ZEB1 in CRCs depended on simultaneous high levels of the Wnt antagonist DKK1, whose expression was transcriptionally activated by ZEB1. In cancer cells with mutant TP53, ZEB1 blocked the formation of senescence-associated heterochromatin foci at the onset of senescence by triggering a new regulatory cascade that involves the subsequent activation of DKK1, mutant p53, Mdm2 and CtBP to ultimately repress macroH2A1 (H2AFY). In a transgenic mouse model of colon cancer, partial downregulation of Zeb1 was sufficient to induce H2afy and to trigger in vivo tumour senescence, thus resulting in reduced tumour load and improved survival. The capacity of ZEB1 to induce tumourigenesis in a xenograft mouse model requires the repression of H2AFY by ZEB1. Lastly, the worst survival effect of ZEB1 in patients with CRC ultimately depends on low expression of H2AFY and of senescence-associated genes. CONCLUSIONS: The tumourigenic capacity of ZEB1 depends on its inhibition of cancer cell senescence through the activation of a herein identified new molecular pathway. These results set ZEB1 as a potential target in therapeutic strategies aimed at inducing senescence.
dc.relation.ispartof urn:issn:0017-5749
dc.title ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1.
dc.type Journal Article 2017-04-26T09:54:53Z
dc.language.rfc3066 en
dc.identifier.mtmt 3211207
dc.identifier.wos WOS:000396419800014
dc.identifier.pubmed 27965283
dc.contributor.department SE/AOK/K/II. Sz. Gyermekgyógyászati Klinika
dc.contributor.institution Semmelweis Egyetem

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