Journal Article

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

Downward, J, Staudt, L M, Wang, Y, Wright, G, Ngo, V N, Marani, M, Yang, Y

2010

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/395 / 631/80/84/2176 / 692/699/67/1504/1885 / Apoptosis / Biological and medical sciences / Cancer / Cell Biology / Cell Line, Tumor / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Cellular biology / Chemoresistance / Colon cancer / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - therapy / Development and progression / Fundamental and applied biological sciences. Psychology / Gastroenterology. Liver. Pancreas. Abdomen / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Gene mutations / Genes, ras / Genetic aspects / Genetic transformation / Genetics / HCT116 Cells / Health aspects / Human Genetics / Humans / Internal Medicine / Medical sciences / Medicine / Medicine & Public Health / Mesenchyme / Molecular and cellular biology / Molecular genetics / Mutants / Mutation / Oncology / original-article / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins p21(ras) / Radioresistance / Ras genes / ras Proteins - genetics / ras Proteins - metabolism / Ribonucleic acid / Risk factors / RNA / RNA-mediated interference / Signal Transduction / Snail Family Transcription Factors / Snail protein / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus / Transcription / Transcription Factors - biosynthesis / Transcription Factors - genetics / Transcription Factors - metabolism / Transcription. Transcription factor. Splicing. Rna processing / Tumor cell lines / Tumors / Zinc finger proteins / Zinc Fingers - genetics