The ZEB2‐dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer

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...

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Published in:	Molecular oncology Vol. 15; no. 8; pp. 2065 - 2083
Main Authors:	Sreekumar, Rahul, Al‐Saihati, Hajir, Emaduddin, Muhammad, Moutasim, Karwan, Mellone, Massimiliano, Patel, Ashish, Kilic, Seval, Cetin, Metin, Erdemir, Sule, Navio, Marta Salgado, Lopez, Maria Antonette, Curtis, Nathan, Yagci, Tamer, Primrose, John N., Price, Brendan D., Berx, Geert, Thomas, Gareth J., Tulchinsky, Eugene, Mirnezami, Alex, Sayan, A. Emre
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-08-2021 John Wiley and Sons Inc Wiley
Subjects:	Adjuvant treatment Animals Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis Automation Biomarkers Cancer Cancer therapies Cell Line, Tumor Chemoresistance Chemotherapy Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology DNA repair DNA Repair - genetics DNA-Binding Proteins - genetics Drug Resistance, Neoplasm EMT Endonucleases - genetics Epithelial-Mesenchymal Transition - genetics ERCC1 ERCC1 gene ERCC1 protein Fluorouracil - therapeutic use Gene expression Genes Genetic aspects Genetic transcription Humans Leucovorin - therapeutic use Liver Liver Neoplasms - secondary Mesenchyme Metastases Mice Mortality Neomycin Nucleotide excision repair Oncology, Experimental Organoplatinum Compounds - therapeutic use Oxaliplatin Patients Prognosis Stem cells Surgery Transcription Transcription, Genetic Tumors Xenograft Model Antitumor Assays ZEB2 Zinc Finger E-box Binding Homeobox 2 - physiology United Kingdom United Kingdom > UK United States > US oxaliplatin ZEB2 DNA repair EMT ERCC1
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Summary:	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. Here, we show that the expression of ZEB2 marks reduced overall and disease‐free survival in primary and secondary colorectal cancers (CRCs). ZEB2 overexpression promoted chemoresistance to oxaliplatin in vitro and in vivo by transcriptionally activating nucleotide excision repair genes ERCC1 and ERCC4. Overall ZEB2 is a promising biomarker predicting both therapy response and metastatic ability of CRCs.
Bibliography:	Rahul Sreekumar and Hajir Al‐Saihati contributed equally as first authors ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1574-7891 1878-0261
DOI:	10.1002/1878-0261.12965