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ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1.
- Source :
-
Gut [Gut] 2017 Apr; Vol. 66 (4), pp. 666-682. Date of Electronic Publication: 2016 Dec 13. - Publication Year :
- 2017
-
Abstract
- Objective: Understand the role of ZEB1 in the tumour initiation and progression beyond inducing an epithelial-to-mesenchymal transition.<br />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.<br />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.<br />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.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
- Subjects :
- Alcohol Oxidoreductases genetics
Alcohol Oxidoreductases metabolism
Animals
Cell Line, Tumor
Cell Survival genetics
Cellular Senescence genetics
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Gene Expression Regulation, Neoplastic
Heterografts
Histones metabolism
Humans
Intercellular Signaling Peptides and Proteins metabolism
Mice
Mice, Transgenic
Mutation
Proto-Oncogene Proteins c-mdm2 genetics
Proto-Oncogene Proteins c-mdm2 metabolism
Survival Rate
Transcription, Genetic
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Up-Regulation
Wnt Signaling Pathway
Zinc Finger E-box-Binding Homeobox 1 metabolism
Carcinogenesis genetics
Colonic Neoplasms genetics
Colonic Neoplasms metabolism
Histones genetics
Intercellular Signaling Peptides and Proteins genetics
Zinc Finger E-box-Binding Homeobox 1 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 66
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 27965283
- Full Text :
- https://doi.org/10.1136/gutjnl-2015-310838