Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells.
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.
Wang
Y
Y
Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK.
Ngo
V N
VN
Marani
M
M
Yang
Y
Y
Wright
G
G
Staudt
L M
LM
Downward
J
J
D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D045325:HCT116 Cells; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D016335:Zinc Fingers / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins