SnoN oncoprotein enhances estrogen receptor-α transcriptional activity

Estrogen receptor-alpha (ER alpha) and transforming growth factor-beta (TGF-beta) signaling pathways are essential regulators during mammary gland development and tumorigenesis. Ski-related novel gene (SnoN) is an oncoprotein and a negative feedback inhibitor of TGF-beta signaling. We have previously reported that low expression of SnoN in ER alpha positive breast carcinomas is associated with favorable prognosis (Zhang et al. Cancer Res. (2003) 63, 5005-5010). Here we have studied the mechanism of a possible cross-talk between ER alpha and SnoN. We find that SnoN interacts with the estrogen-activated form of ER alpha in the nucleus. SnoN contains two highly conserved nuclear receptor binding LxxLL-like motifs and we show that mutations in these motifs reduce the interaction of SnoN with ER alpha. Over-expression of SnoN enhanced the transcriptional activity of ER alpha in estrogen response element (ERE)-reporter assays, augmented the expression of several ER alpha target genes and increased the proliferation of MCF7 breast carcinoma cells in an estrogen-dependent manner. Chromatin immunoprecipitation demonstrated that SnoN interacts with ER alpha at the TTF1 (pS2) gene promoter. Conversely, silencing of SnoN reduced both ERE-reporter activity and the expression of ER alpha target genes in MCF7 and T-47D breast cancer cells. Histone deacetylase inhibition increased the level of SnoN and SnoN-dependent enhancement of ER alpha-dependent transcription and SnoN supported the recruitment of p300 histone acetylase to ER alpha. This study reveals a novel mechanism that interconnects ER alpha and TGF-beta signaling pathways by SnoN. Accordingly, the results indicate that high SnoN level promotes ER alpha signaling and possibly breast cancer progression. (C) 2012 Elsevier Inc. All rights reserved.