Open AccessCritical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells
Author(s) -
Yihua Wang,
Vu N. Ngo,
Michela Marani,
Yandan Yang,
George W. Wright,
Louis M. Staudt,
Julian Downward
Publication year - 2010
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/onc.2010.218
Subject(s) - biology , kras , repressor , cancer research , carcinogenesis , epithelial–mesenchymal transition , mutant , small hairpin rna , cancer , gene , colorectal cancer , genetics , gene expression , downregulation and upregulation , rna
Activating mutations in the KRAS gene are among the most prevalent genetic changes in human cancers. To identify synthetic lethal interactions in cancer cells harbouring mutant KRAS, we performed a large-scale screen in isogenic paired colon cancer cell lines that differ by a single allele of mutant KRAS using an inducible short hairpin RNA interference library. Snail2, a zinc finger transcriptional repressor encoded by the SNAI2 gene, was found to be selectively required for the long-term survival of cancer cells with mutant KRAS that have undergone epithelial-mesenchymal transition (EMT), a transdifferentiation event that is frequently seen in advanced tumours and is promoted by RAS activation. Snail2 expression is regulated by the RAS pathway and is required for EMT. Our findings support Snail2 as a possible target for the treatment of the broad spectrum of human cancers of epithelial origin with mutant RAS that have undergone EMT and are characterized by a high degree of chemoresistance and radioresistance.