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.
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Contributors OdB performed most of the experimental work in the study, designed and interpreted experiments and wrote the manuscript. BG carried out the bioinformatics analysis of arrays for survival and gene expression. MJFA facilitated the collection of human samples of colorectal carcinomas and conducted the pathological analysis of their immunostaining. EST, LSM and LS performed some of the experimental work. AEA and GR assisted in the setting of the xenograft mouse model. JIC, DSD and AC supplied critical materials to the study. AP conceived and supervised the study, designed and interpreted experiments, obtained funding and wrote the manuscript. All authors critically reviewed the manuscript.
Funding The different parts of this study were independently funded by grants to AP from Fundació La Marató de TV3 (201330.10), Ministry of Economy and Competitiveness (BFU2010-15163 and SAF2014-52874-R, the latter part of the 2013–2016 National Scientific and Technical Research and Innovation Plan, that is co-financed by the European Regional Development Fund of the European Union Commission), Avon Foundation S.A.U. (ACSAU), Catalan Agency for Management of University and Research Grants (AGAUR, 2014-SGR-475), Leukemia Research Foundation (Hollis Brownstein Grants 2014), Academy of Medical and Health Sciences of Catalonia and the Balearic Islands (Recerca Bàsica 2013), European Commission of the European Union, Olga Torres Foundation, La Caixa Foundation (LCF) and Spanish Association Against Cancer. OdB's stipend was subsequently funded by a PhD scholarship from the Spanish Ministry of Education, Culture and Sports (MECS) (FPU programme, AP2010-5489), AGAUR and a scholarship from University of Barcelona. EST's salary was subsequently funded by the grants from LCF and ACSAU, a CIBERehd postdoctoral contract and a Miguel Servet contract (MS13/00200) from Instituto de Salud Carlos III. LSM, LS and AEA are also recipients of PhD scholarships from the MECS (FPU14/06217, AP2010-4495 and FPU12/05690, respectively).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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