The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer
Sreekumar R. Al-Saihati H. Emaduddin M. Moutasim K. Mellone M. Patel A. Kilic S. Cetin M. Erdemir S. Navio M.S. Lopez M.A. Curtis N. Yagci T. Primrose J.N. Price B.D. Berx G. Thomas G.J. Tulchinsky E. Mirnezami A. Sayan A.E.
August 2021John Wiley and Sons Ltd
Molecular Oncology
2021#15Issue 82065 - 2083 pp.
Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)-inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease-free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2-dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1-overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2-ERCC1 axis is a key determinant of chemoresistance in CRC.
DNA repair , EMT , ERCC1 , oxaliplatin , ZEB2
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Cancer Sciences Division, University of Southampton, United Kingdom
College of Applied Medical Sciences, University of Hafr Al-Batin, Saudi Arabia
Department of Molecular Biology and Genetics, Gebze Technical University, Turkey
Department of Surgery, Southampton University Hospital NHS Trust, United Kingdom
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
Molecular Cellular Oncology Lab, Department for Biomedical Molecular Biology, Ghent University, Belgium
Cancer Research Institute Ghent (CRIG), Belgium
Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan
Cancer Sciences Division
College of Applied Medical Sciences
Department of Molecular Biology and Genetics
Department of Surgery
Department of Radiation Oncology
Molecular Cellular Oncology Lab
Cancer Research Institute Ghent (CRIG)
Department of Biomedical Sciences
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