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Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells
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.
KRAS, synthetic lethal, oncogene addiction, epithelial–mesenchymal transition
0950-9232
4658-4670
Wang, Y.
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Ngo, V.N.
61109902-aa45-4450-9486-1d224333d245
Marani, M.
d14d6c08-59bd-4cae-b39f-37108960433e
Yang, Y.
0c661323-7e23-41c6-a9a2-b4479fd74ef1
Wright, G.
9cf8d03e-790c-4b94-80aa-708e03544740
Staudt, L.M.
59b3a8fc-c5c3-45ca-b57c-1cc144b6d86f
Downward, J.
0d5a0a0d-7cab-4322-9afb-913aa19db49b
Wang, Y.
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Ngo, V.N.
61109902-aa45-4450-9486-1d224333d245
Marani, M.
d14d6c08-59bd-4cae-b39f-37108960433e
Yang, Y.
0c661323-7e23-41c6-a9a2-b4479fd74ef1
Wright, G.
9cf8d03e-790c-4b94-80aa-708e03544740
Staudt, L.M.
59b3a8fc-c5c3-45ca-b57c-1cc144b6d86f
Downward, J.
0d5a0a0d-7cab-4322-9afb-913aa19db49b

Wang, Y., Ngo, V.N., Marani, M., Yang, Y., Wright, G., Staudt, L.M. and Downward, J. (2010) Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells. Oncogene, 29 (33), 4658-4670. (doi:10.1038/onc.2010.218).

Record type: Article

Abstract

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.

Full text not available from this repository.

More information

Accepted/In Press date: 6 May 2010
e-pub ahead of print date: 21 June 2010
Published date: 19 August 2010
Keywords: KRAS, synthetic lethal, oncogene addiction, epithelial–mesenchymal transition
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 385904
URI: http://eprints.soton.ac.uk/id/eprint/385904
ISSN: 0950-9232
PURE UUID: a1da1fba-de11-4303-9989-a16ad5ecae05
ORCID for Y. Wang: ORCID iD orcid.org/0000-0001-5561-0648

Catalogue record

Date deposited: 26 Jan 2016 09:52
Last modified: 05 Nov 2019 01:34

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