Title: Abstract 3899: A coactivator role of CARM1 for the dysregulated β-catenin activity in colorectal cancer cell growth and gene expression
Abstract: Abstract Aberrant activation of Wnt/β-catenin signaling is recognized as a critical factor in the etiology of colorectal cancer. Evidence has suggested that dysregulated β-catenin activity is associated with the majority of colon cancers via activation of the expression of Wnt regulated oncogenes. In the nucleus, β-catenin regulates transcription by recruiting additional secondary coactivators. These secondary coactivators all have distinct and unique functions on Wnt/β-catenin target gene activation. For instance, CCAR1 (Cell Cycle and Apoptosis Regulator 1) has been shown to be important for the stable occupancy of β-catenin at the promoter of a Wnt target gene, and depletion of CCAR1 inhibits expression of several Wnt/β-catenin target genes and suppresses anchorage-independent growth of colon cancer cells (Ou CY et al. Journal of Biological Chemistry 2009;284(31);20629-20637). Here, we show that CARM1 (coactivator-associated-protein-arginine-methyltransferase 1) interacts with β-catenin and positively modulates β-catenin-mediated gene expression. In colorectal cancer cells, which have constitutively high Wnt/β-catenin activity, depletion of CARM1 inhibits the expression of Wnt/β-catenin-mediated oncogenes and suppresses anchorage-independent growth. In colorectal cancer cells that do not have constitutively high Wnt/β-catenin activity, we found that activation of Wnt/β-catenin signaling by treatment with Wnt3a increased the expression of a subset of Wnt target genes. Utilizing these cells, we demonstrated that CARM1 is specifically required for the expression of these Wnt3a-induced targets. Upon Wnt3a stimulation, CARM1-dependent dimethylation of histone H3 arginine (Arg) 17, at a Wnt-regulated promoter, is associated with the recruitment of both β-catenin and CARM1. Arg17 dimethylation by Wnt3a ligands is compromised by CARM1 knockdown, whereas Wnt3a-induced β-catenin recruitment is not affected. Finally, in a nude mouse xenograft model, compared with CARM1 knockdown cells, wild type HT29 tumor xenografts grow significantly faster. We conclude that CARM1 is an important modulator of Wnt/β-catenin transcription and may represent a novel target for therapeutic intervention in cancers involving aberrantly activated Wnt/β-catenin signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3899.
Publication Year: 2010
Publication Date: 2010-04-01
Language: en
Type: article
Indexed In: ['crossref']
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