Abstract 947: Molecular mechanism of WBP-2 coactivation function in estrogen receptor transactivation

The link between breast cancer and Estrogen Receptor alpha (ERα) is well established. The ERα is a ligand-inducible transcription factor that, upon binding to the hormone estrogen, regulates the expression of a variety of genes mainly involved in cell proliferation. Coactivators are proteins recruited by the hormone-activated receptor, which enhance the ERα transactivation functions acting as chromatin remodeling enzymes or adaptors between ERα and the transcriptional machinery. Our laboratory has previously identified WBP-2 (WW-domain binding protein 2) as bona fide coactivator of ERα. However, the molecular mechanism underlying WBP-2 coactivation function is not clear yet. In this study we investigate the mechanism by which WBP-2 acts as a coactivators of ERα. Our data show that knockdown of WBP-2 protein is associated with reduced expression of the ERα target gene pS2. Conversely, over-expression of the same protein results in increased pS2 expression. In order to clarify the mechanism governing these outcomes, we performed chromatin immunoprecipitation (ChIP) assays under WBP-2 knockdown conditions. We demonstrate here that WBP-2 binds to the pS2 promoter, and its knockdown is associated with decreased recruitment of the phosphorylated form of RNA PolII (associated with active transcription). Under similar conditions, the histone acetyl transferase p300 also exhibits reduced recruitment to the same promoter. Accordingly, decreased recruitment of p300 correlates with decreased histone acetylation. Collectively, our data indicate that WBP-2 enhances ERα transactivation function by facilitating the recruitment of a histone modifier enzyme that favors a relaxed chromatin structure permissive of transcription. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 947. doi:1538-7445.AM2012-947