ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1
- Oriol de Barrios 1, Balázs Győrffy 2, María Jesús Fernández-Aceñero 3,4, Ester Sánchez-Tilló 1, Lidia Sánchez-Moral 1, Laura Siles 1, Anna Esteve-Arenys 5, Gaël Roué 5, José I Casal 6, Douglas S Darling 7, Antoni Castells 8,9, Antonio Postigo 1,9,10,11
- 1Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
- 2Lendület Cancer Biomarker Research Group, MTA TTK and 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
- 3Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain.
- 4Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain.
- 5Lymphoma Group, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
- 6Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
- 7Department of Oral Immunology and Infectious Diseases and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, Kentucky, USA.
- 8Institute of Metabolic and Digestive Diseases, Hospital Clínic, Barcelona, Spain.
- 9Gastrointestinal and Pancreatic Oncology Team, Biomedical Research Networking Centers in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Barcelona, Spain.
- 10Molecular Targets Program, James Graham Brown Cancer Center, Louisville, Kentucky, USA.
- 11ICREA, Barcelona, Spain.
- 0Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
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View abstract on PubMed
Summary
This summary is machine-generated.ZEB1 promotes tumor growth by blocking senescence in colorectal cancer (CRC) cells. Inhibiting ZEB1 can restore senescence, reduce tumor load, and improve survival, highlighting ZEB1 as a therapeutic target.
Area Of Science
- Oncology
- Molecular Biology
- Cancer Genetics
Background
- The transcription factor ZEB1 is linked to poor prognosis in various cancers, including colorectal carcinoma (CRC).
- ZEB1's role in tumor initiation and progression extends beyond epithelial-to-mesenchymal transition.
Purpose Of The Study
- To elucidate the role of ZEB1 in tumor initiation and progression.
- To understand the molecular mechanisms by which ZEB1 influences tumor development and patient survival.
Main Methods
- Survival analysis in CRC patients.
- In vivo studies using transgenic and xenograft mouse models.
- Gene expression arrays, immunostaining, and molecular assays to analyze gene and protein regulation.
Main Results
- ZEB1-driven poor survival in CRC correlates with high DKK1 levels, transcriptionally activated by ZEB1.
- In TP53-mutant cancer cells, ZEB1 inhibits senescence by repressing macroH2A1 (H2AFY) via a pathway involving DKK1, p53, Mdm2, and CtBP.
- Downregulating Zeb1 in a mouse model induced senescence, reduced tumor load, and improved survival.
- ZEB1's tumorigenic capacity requires H2AFY repression.
Conclusions
- ZEB1 promotes tumorigenesis by inhibiting cancer cell senescence through a novel molecular pathway.
- ZEB1's ability to block senescence positions it as a potential therapeutic target for inducing senescence in cancer treatment.
Keywords:
COLORECTAL CARCINOMA
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