Wang, Y, Ngo, VN, Marani, M, Yang, Y, Wright, G, Staudt, LM et al.. Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells. Oncogene 29: 4658-4670

Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK.
Oncogene (Impact Factor: 8.46). 08/2010; 29(33):4658-70. DOI: 10.1038/onc.2010.218
Source: PubMed


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.

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Available from: Yihua Wang, Mar 18, 2014
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    • "Therefore, network inference approaches could prove effectively useful to uncover new modules and the master regulators that orchestrate malignant transformation. Among the TFs ranked at the top of the list of increased connectivity, our analysis identified colorectal cancer related genes: two oncogenes (MAFB [39] and GLI2 [40]), proliferation-related genes (NOTCH3 [41] and TGFB1 [42]), epithelial-mesenchymal transition (SNAI2 [43]) and the Wnt signaling genes SFRP4, TWIST1, SMARCA4 and DKK3, potentially involved in colorectal cancer angiogenesis [44]. One remarkable gene with increased activity in the tumor network was GREM1. "
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    ABSTRACT: Dysregulation of transcriptional programs leads to cell malfunctioning and can have an impact in cancer development. Our study aims to characterize global differences between transcriptional regulatory programs of normal and tumor cells of the colon. Affymetrix Human Genome U219 expression arrays were used to assess gene expression in 100 samples of colon tumor and their paired adjacent normal mucosa. Transcriptional networks were reconstructed using ARACNe algorithm using 1,000 bootstrap replicates consolidated into a consensus network. Networks were compared regarding topology parameters and identified well-connected clusters. Functional enrichment was performed with SIGORA method. ENCODE ChIP-Seq data curated in the hmChIP database was used for in silico validation of the most prominent transcription factors. The normal network contained 1,177 transcription factors, 5,466 target genes and 61,226 transcriptional interactions. A large loss of transcriptional interactions in the tumor network was observed (11,585; 81% reduction), which also contained fewer transcription factors (621; 47% reduction) and target genes (2,190; 60% reduction) than the normal network. Gene silencing was not a main determinant of this loss of regulatory activity, since the average gene expression was essentially conserved. Also, 91 transcription factors increased their connectivity in the tumor network. These genes revealed a tumor-specific emergent transcriptional regulatory program with significant functional enrichment related to colorectal cancer pathway. In addition, the analysis of clusters again identified subnetworks in the tumors enriched for cancer related pathways (immune response, Wnt signaling, DNA replication, cell adherence, apoptosis, DNA repair, among others). Also multiple metabolism pathways show differential clustering between the tumor and normal network. These findings will allow a better understanding of the transcriptional regulatory programs altered in colon cancer and could be an invaluable methodology to identify potential hubs with a relevant role in the field of cancer diagnosis, prognosis and therapy.
    Full-text · Article · Sep 2014 · BMC Cancer
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    • "Direct inhibition of RAS activity has not met with great success (Downward, 2003), but targeting of downstream signalling molecules (such as RAF and MEK) holds promise (Montagut and Settleman, 2009). In addition, synthetic lethality screens have identified potential targets selective to RAS mutant cells (Wang et al., 2010). We did not find statistically significant differences in the CTL recognition of H Mu and H WT cells. "
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    ABSTRACT: Mutations in the RAS family of oncogenes are highly prevalent in human cancer and, amongst its manifold effects, oncogenic RAS impairs the expression of components of the antigen presentation pathway. This allows evasion of cytotoxic T lymphocytes (CTL). CTL and natural killer (NK) cells are reciprocally regulated by MHC class I molecules and any gain in CTL recognition obtained by therapeutic inactivation of oncogenic RAS may be offset by reduced NK cell activation. We have investigated the consequences of targeted inactivation of oncogenic RAS on the recognition by both CTL and NK cells. Inactivation of oncogenic RAS, either by genetic deletion or inactivation with an inducible intracellular domain antibody (iDAb), increased MHC class I expression in human colorectal cell lines. The common RAS mutations, at codons 12, 13 and 61, all inhibited antigen presentation. Although MHC class I modulates the activity of both CTL and NK cells, the enhanced MHC class I expression resulting from inactivation of mutant KRAS did not significantly affect the in vitro recognition of these cell lines by either class of cytotoxic lymphocyte. These results show that oncogenic RAS and its downstream signalling pathways modulate the antigen presentation pathway and that this inhibition is reversible. However, the magnitude of these effects was not sufficient to alter the in vitro recognition of tumour cell lines by either CTL or NK cells.
    Full-text · Article · Dec 2013 · Molecular Immunology
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    • "ASPP2 phosphorylation was rapid and transient as 3 hours after EGF stimulation phosphorylated ASPP2 was barely detectable. Moreover, with another different phospho-ASPP2 antibody, ES1, ASPP2 phosphorylation was also observed in a human colon cancer cell line HKe3 ER:HRASV12 cells, in which RAS activation is induced upon the addition of 4-hydroxytamoxifen (4-OHT) [2,10,11] (Figure 1E). The phospho-specific antibody for ASPP2 is specific as knockdown of ASPP2 resulted in a lack of detection of phospho-ASPP2. "
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    ABSTRACT: We reported recently that apoptosis-stimulating protein of p53 (ASPP) 2, an activator of p53, co-operates with oncogenic RAS to enhance the transcription and apoptotic function of p53. However, the detailed mechanism remains unknown. Here we show that ASPP2 is a novel substrate of mitogen-activated protein kinase (MAPK). Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes. In contrast, an ASPP2 phosphorylation mutant exhibits reduced p53 binding and fails to enhance transactivation and apoptosis. Thus phosphorylation of ASPP2 by RAS/MAPK pathway provides a novel link between RAS and p53 in regulating apoptosis.
    Full-text · Article · Dec 2013 · PLoS ONE
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