title: 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.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Chen-Yin
authors.initials: CY
authors.lastname: Ou
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: LaBonte
authors.forename: Philipp C
authors.initials: PC
authors.lastname: Manegold
authors.forename: Alex Yick-Lun
authors.initials: AY
authors.lastname: So
authors.forename: Irina
authors.initials: I
authors.lastname: Ianculescu
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Gerke
authors.forename: Keith R
authors.initials: KR
authors.lastname: Yamamoto
authors.forename: Robert D
authors.initials: RD
authors.lastname: Ladner
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.forename: Jeong Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D006657:Histones; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1