A coactivator role of CARM1 in the dysregulation of β-catenin activity in colorectal cancer cell growth and gene expression.

Abstract

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.

• Authors: Chen-Yin Ou, Melissa J LaBonte, Philipp C Manegold, Alex Yick-Lun So, Irina Ianculescu, Daniel S Gerke, Keith R Yamamoto, Robert D Ladner, Michael Kahn, Jeong Hoon Kim, Michael R Stallcup
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 9 Issue 5 Pg. 660-70 (May 2011) ISSN: 1557-3125 [Electronic] United States
• PMID: 21478268 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Histones
• LEF1 protein, human
• Lymphoid Enhancer-Binding Factor 1
• Transcription Factors
• Wnt Proteins
• beta Catenin
• Protein-Arginine N-Methyltransferases
• coactivator-associated arginine methyltransferase 1

Topics

• Cell Line, Tumor
• Cell Proliferation
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Histones (genetics, metabolism)
• Humans
• Lymphoid Enhancer-Binding Factor 1 (metabolism)
• Promoter Regions, Genetic
• Protein-Arginine N-Methyltransferases (genetics, metabolism)
• Signal Transduction (genetics)
• Transcription Factors (genetics, metabolism)
• Transcriptional Activation
• Wnt Proteins (metabolism)
• beta Catenin (metabolism)