Molecular Cancer Biology Program, Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland.
Cell Signal. 2012 Apr;24(4):922-30. doi: 10.1016/j.cellsig.2011.12.015. Epub 2011 Dec 29.
Estrogen receptor-α (ERα) and transforming growth factor-beta (TGF-β) 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-β signaling. We have previously reported that low expression of SnoN in ERα 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 ERα and SnoN. We find that SnoN interacts with the estrogen-activated form of ERα 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 ERα. Over-expression of SnoN enhanced the transcriptional activity of ERα in estrogen response element (ERE)-reporter assays, augmented the expression of several ERα target genes and increased the proliferation of MCF7 breast carcinoma cells in an estrogen-dependent manner. Chromatin immunoprecipitation demonstrated that SnoN interacts with ERα at the TTF1 (pS2) gene promoter. Conversely, silencing of SnoN reduced both ERE-reporter activity and the expression of ERα target genes in MCF7 and T-47D breast cancer cells. Histone deacetylase inhibition increased the level of SnoN and SnoN-dependent enhancement of ERα-dependent transcription and SnoN supported the recruitment of p300 histone acetylase to ERα. This study reveals a novel mechanism that interconnects ERα and TGF-β signaling pathways by SnoN. Accordingly, the results indicate that high SnoN level promotes ERα signaling and possibly breast cancer progression.
雌激素受体-α（ERα）和转化生长因子-β（TGF-β）信号通路是乳腺发育和肿瘤发生过程中的重要调节因子。Ski 相关新型基因（SnoN）是一种癌蛋白，也是 TGF-β信号的负反馈抑制剂。我们之前的研究报告显示，ERα阳性乳腺癌中 SnoN 的低表达与良好的预后相关（Zhang 等人，Cancer Res.（2003）63，5005-5010）。在这里，我们研究了 ERα 和 SnoN 之间可能存在的交叉对话机制。我们发现 SnoN 在核内与雌激素激活的 ERα 相互作用。SnoN 包含两个高度保守的核受体结合 LxxLL 样基序，我们证明这些基序中的突变会降低 SnoN 与 ERα 的相互作用。SnoN 的过表达增强了 ERα 在雌激素反应元件（ERE）报告基因检测中的转录活性，增加了几个 ERα 靶基因的表达，并以雌激素依赖的方式增加 MCF7 乳腺癌细胞的增殖。染色质免疫沉淀实验表明，SnoN 在 TTF1（pS2）基因启动子处与 ERα 相互作用。相反，SnoN 的沉默降低了 MCF7 和 T-47D 乳腺癌细胞中 ERE 报告基因的活性和 ERα 靶基因的表达。组蛋白去乙酰化酶抑制增加了 SnoN 的水平，SnoN 依赖性增强了 ERα 依赖性转录，并且 SnoN 支持 p300 组蛋白乙酰转移酶向 ERα 的募集。这项研究揭示了一种新的机制，通过 SnoN 将 ERα 和 TGF-β 信号通路相互连接。因此，研究结果表明，高水平的 SnoN 促进 ERα 信号转导，并可能促进乳腺癌的进展。
