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De Barrios OAuthorSánchez-Tilló EAuthorSánchez-Moral LAuthorSiles LAuthorEsteve-Arenys AAuthorRoue GAuthorCastells ACorresponding AuthorPostigo ACorresponding Author
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ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1

Publicated to:Gut. 66 (4): 666-682 - 2017-04-01 66(4), DOI: 10.1136/gutjnl-2015-310838

Authors: de Barrios, Oriol; Gyorffy, Balazs; Jesus Fernandez-Acenero, Maria; Sanchez-Tillo, Ester; Sanchez-Moral, Lidia; Siles, Laura; Esteve-Arenys, Anna; Roue, Gael; Casal, Jose I; Darling, Douglas S; Castells, Antoni; Postigo, Antonio

Affiliations

Carlos III Hlth Inst ISCIII, Biomed Res Networking Ctr Hepat & Digest Dis CIBE, Gastrointestinal & Pancreat Oncol Team, Barcelona, Spain      CIBEREHD    CIBER - Centro de Investigacion Biomedica en Red       - Author
CSIC, CIB, Dept Cellular & Mol Med, Madrid, Spain      Consejo Superior de Investigaciones Cientificas (CSIC) - Author
Fdn Jimenez Diaz, Univ Hosp, Dept Pathol, Madrid, Spain      Fundacion Jimenez Diaz    Hospital Puerta de Hierro-Majadahonda - Author
Hosp Clin Barcelona, Inst Metab & Digest Dis, Barcelona, Spain      University of Barcelona    Hospital Clinic de Barcelona - Author
Hosp Clin San Carlos, Dept Pathol, Madrid, Spain      Hospital Clinico San Carlos - Author
ICREA, Barcelona, Spain - Author
IDIBAPS, Dept Hematol & Oncol, Grp Transcript Regulat Gene Express, Barcelona, Spain      IDIBAPS    University of Barcelona    Hospital Clinic de Barcelona - Author
IDIBAPS, Dept Hematol & Oncol, Lymphoma Grp, Barcelona, Spain      IDIBAPS    University of Barcelona    Hospital Clinic de Barcelona - Author
IDIBAPS, Grp Transcript Regulat Gene Express, Casanova 143, Barcelona 08036, Spain.      University of Barcelona    Hospital Clinic de Barcelona    IDIBAPS - Author
James Graham Brown Canc Ctr, Mol Targets Program, Louisville, KY USA       - Author
Semmelweis Univ, Dept Pediat 2, Budapest, Hungary      Semmelweis University - Author
Semmelweis Univ, MTA TTK, Lendulet Canc Biomarker Res Grp, Budapest, Hungary      Semmelweis University - Author
Univ Louisville, Ctr Genet & Mol Med, Louisville, KY 40292 USA      University of Louisville - Author
Univ Louisville, Dept Oral Immunol & Infect Dis, Louisville, KY 40292 USA      University of Louisville - Author
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Abstract

Understand the role of ZEB1 in the tumour initiation and progression beyond inducing an epithelial-to-mesenchymal transition.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.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.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.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/.

Keywords
cellular senescencecolon-cancercolorectal-cancerdown-regulationgene-expressionheterochromatin focimutant p53replicative senescencezeb proteinsAlcohol oxidoreductasesAnimalsC-terminal binding proteinCarcinogenesisCell line, tumorCell survivalCellular senescenceColonic neoplasmsColorectal carcinomaDkk1 protein, mouseDna-binding proteinsEpithelial-mesenchymal transitionGene expression regulation, neoplasticHeterograftsHistonesHumansIntercellular signaling peptides and proteinsMacroh2a histoneMdm2 protein, mouseMiceMice, transgenicMutationProto-oncogene proteins c-mdm2Survival rateTranscription, geneticTumor suppressor protein p53Up-regulationWnt signaling pathwayZeb1 protein, humanZeb1 protein, mouseZinc finger e-box-binding homeobox 1

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Gut due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2017, it was in position 3/80, thus managing to position itself as a Q1 (Primer Cuartil), in the category Gastroenterology & Hepatology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations from Scopus Elsevier, it yields a value for the Field-Weighted Citation Impact from the Scopus agency: 1.19, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 6.21 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-23, the following number of citations:

  • WoS: 32
  • Scopus: 36
  • Europe PMC: 24
  • Google Scholar: 46
  • OpenCitations: 29
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-23:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 72.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 72 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 10.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Hungary; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (de Barrios Barri, Oriol) and Last Author (Postigo, Antonio).

the authors responsible for correspondence tasks have been Castells Garangou, Antoni and Postigo, Antonio.