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 protein 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 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) which 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.

Protein arginine methyltransferase CARM1 attenuates the paraspeckle-mediated nuclear retention of mRNAs containing IRAlus

“…The plasmids pEGFP-SC-Nicn1-Alu (IRAlus) and pEGFP-SC-Lin28-Alu (IRAlus) have been described . CARM1 knockdown was carried out as described (Ou et al 2011), and stable HeLa and HEK293 lines were generated. To knock down p54 nrb , the sequence "GCAGG CGAAGTCTTCATTCAT" was inserted into pLVTHM vector with Mlu1 and Cla1, and the construct was packaged into lentivirus to infect HeLa cells.…”

Protein Arginine Methyltransferase 7 Regulates Cellular Response to DNA Damage by Methylating Promoter Histones H2A and H4 of the Polymerase δ Catalytic Subunit Gene, POLD1

“…2). ChIP assays revealed that although PRMT1 and PRMT4 were enriched at known target promoters (29,30), their binding to PRMT7 target promoters was unaffected in both control and PRMT7 knockdown cells. These results indicate that both of these co-activator enzymes are not involved during transcriptional derepression of PRMT7 target DNA repair genes.…”

Inhibition of androgen receptor and β-catenin activity in prostate cancer

“…To test this idea, we determined if C3 affected occupancy of commonly acknowledged coactivators of AR and β-catenin including p300, glutamate receptor-interacting protein 1 (GRIP1), coactivator-associated arginine methyltransferase 1 (CARM1), and BRG1 on AR target genes. These coactivators were recruited to both AR and β-catenin/ TCF-binding sites (33)(34)(35)(36), and the physical interaction between some of the coactivators and AR or β-catenin has been shown (9,28,37,38). GRIP1 and p300 are histone acetyltransferases (39,40), and BRG1 is a core component of the SWI/SNF chromatinremodeling complex (41).…”