Arginine methylation is a common post-translational modification that has been strongly implicated in transcriptional regulation. The arginine methyltransferases (PRMTs) were first reported as transcriptional coactivators for the estrogen and androgen receptors. Compounds that inhibit these enzymes will provide us with valuable tools for dissecting the roles of these enzymes in cells, and will possibly also have therapeutic applications. In order to identify such inhibitors of the PRMTs, we have previously performed a high-throughput screen using a small molecule library. These compounds were named arginine methyltransferase inhibitors (AMIs). The majority of these inhibitors were polyphenols, and one in particular (AMI-18) shared additional features with a group of known xenoestrogens. We, thus, tested a panel of xenoestrogens and found that a number of them possess the ability to inhibit PRMT activity, in vitro. These inhibitors primarily target CARM1, and include licochalcone A, kepone, benzyl 4-hydroxybenzoate, and tamoxifen. We developed a cell-based reporter system for CARM1 activity, and showed that tamoxifen (IC(50) =30 μM) inhibits this PRMT. The ability of these compounds to regulate the activity of transcriptional coactivators may be an unappreciated mechanism of action for xenoestrogens, and might also explain the efficacy of high-dose tamoxifen treatment on estrogen receptor negative cancers.
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