Open AccessThe ZEB2‐dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer
Author(s) -
Sreekumar Rahul,
AlSaihati 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
Publication year - 2021
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12965
Subject(s) - ercc1 , oxaliplatin , colorectal cancer , oncology , medicine , folfox , biomarker , cancer research , chemotherapy , nucleotide excision repair , cancer , biology , dna repair , gene , genetics
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.