Oriol de Barrios1, Balázs Győrffy2, María Jesús Fernández-Aceñero3,4, Ester Sánchez-Tilló1, Lidia Sánchez-Moral1, Laura Siles1, Anna Esteve-Arenys5, Gaël Roué5, José I Casal6, Douglas S Darling7, Antoni Castells8,9, Antonio Postigo1,9,10,11. 1. Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain. 2. Lendület Cancer Biomarker Research Group, MTA TTK and 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary. 3. Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain. 4. Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain. 5. Lymphoma Group, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain. 6. Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain. 7. Department of Oral Immunology and Infectious Diseases and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, Kentucky, USA. 8. Institute of Metabolic and Digestive Diseases, Hospital Clínic, Barcelona, Spain. 9. Gastrointestinal and Pancreatic Oncology Team, Biomedical Research Networking Centers in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Barcelona, Spain. 10. Molecular Targets Program, James Graham Brown Cancer Center, Louisville, Kentucky, USA. 11. ICREA, Barcelona, Spain.
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. 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/.
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. 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/.
Authors: Mir Mohd Faheem; Nathan D Seligson; Syed Mudabir Ahmad; Reyaz Ur Rasool; Sumit G Gandhi; Madhulika Bhagat; Anindya Goswami Journal: Cell Death Discov Date: 2020-06-15