A coactivator role of CARM1 in the dysregulation of β-catenin activity in colorectal cancer cell growth and gene expression
| Autor: | Melissa J. LaBonte, Alex Yick Lun So, Chen-Yin Ou, Robert D. Ladner, Philipp C. Manegold, Daniel S. Gerke, Michael Kahn, Irina Ianculescu, Keith R. Yamamoto, Jeong Hoon Kim, Michael R. Stallcup |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Transcriptional Activation
Cancer Research Protein-Arginine N-Methyltransferases Beta-catenin CARM1 Lymphoid Enhancer-Binding Factor 1 Biology Article Histones Cell Line Tumor Coactivator Humans Promoter Regions Genetic Molecular Biology beta Catenin Cell Proliferation Regulation of gene expression Wnt signaling pathway LRP6 LRP5 Gene Expression Regulation Neoplastic Wnt Proteins Oncology Catenin Cancer research biology.protein Colorectal Neoplasms Signal Transduction Transcription Factors |
| Popis: | Aberrant activation of Wnt/β-catenin signaling, resulting in the expression of Wnt-regulated oncogenes, is recognized as a critical factor in the etiology of colorectal cancer. Occupancy of β-catenin at promoters of Wnt target genes drives transcription, but the mechanism of β-catenin action remains poorly understood. Here, we show that CARM1 (coactivator-associated arginine methyltransferase 1) interacts with β-catenin and positively modulates β-catenin–mediated gene expression. In colorectal cancer cells with constitutively high Wnt/β-catenin activity, depletion of CARM1 inhibits expression of endogenous Wnt/β-catenin target genes and suppresses clonal survival and anchorage-independent growth. We also identified a colorectal cancer cell line (RKO) with a low basal level of β-catenin, which is dramatically elevated by treatment with Wnt3a. Wnt3a also increased the expression of a subset of endogenous Wnt target genes, and CARM1 was required for the Wnt-induced expression of these target genes and the accompanying dimethylation of arginine 17 of histone H3. Depletion of β-catenin from RKO cells diminished the Wnt-induced occupancy of CARM1 on a Wnt target gene, indicating that CARM1 is recruited to Wnt target genes through its interaction with β-catenin and contributes to transcriptional activation by mediating events (including histone H3 methylation) that are downstream from the actions of β-catenin. Therefore, CARM1 is an important positive modulator of Wnt/β-catenin transcription and neoplastic transformation, and may thereby represent a novel target for therapeutic intervention in cancers involving aberrantly activated Wnt/β-catenin signaling. Mol Cancer Res; 9(5); 660–70. ©2011 AACR. |
| Databáze: | OpenAIRE |
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