Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, The George Washington University, Washington, D. C. 20037, USA.
J Biol Chem. 2012 Aug 10;287(33):27843-50. doi: 10.1074/jbc.M112.348474. Epub 2012 Jun 14.
Metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with malignant phenotypic changes contributing to morbidity in the associated diseases. Here we discovered for the first time that MTA1, a master chromatin modifier, transcriptionally represses the expression of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, by recruiting class II histone deacetylase 4 (HDAC4) along with the transcription factor Yin-Yang 1 (YY1) onto the PTEN promoter. We also found evidence of an inverse correlation between the expression levels of MTA1 and PTEN in physiologically relevant breast cancer microarray datasets. We found that MTA1 up-regulation leads to a decreased expression of PTEN protein and stimulation of PI3K as well as phosphorylation of its signaling targets. Accordingly, selective down-regulation of MTA1 in breast cancer cells increases PTEN expression and inhibits stimulation of the PI3K/AKT signaling. Collectively, these findings provide a mechanistic role for MTA1 in transcriptional repression of PTEN, leading to modulation of the resulting signaling pathways.
转移相关蛋白 1（MTA1）在人类癌症中广泛过表达，与导致相关疾病发病的恶性表型变化有关。在这里，我们首次发现，作为主要染色质修饰物的 MTA1 通过募集 II 类组蛋白去乙酰化酶 4（HDAC4）和转录因子 Yin-Yang 1（YY1）到 PTEN 启动子上，转录抑制肿瘤抑制基因磷酸酶和张力蛋白同源物（PTEN）的表达。我们还在生理相关的乳腺癌基因芯片数据集发现了 MTA1 和 PTEN 表达水平之间的负相关证据。我们发现，MTA1 的上调导致 PTEN 蛋白表达减少和 PI3K 的刺激以及其信号靶标的磷酸化。因此，乳腺癌细胞中 MTA1 的选择性下调增加了 PTEN 的表达并抑制了 PI3K/AKT 信号的刺激。总之，这些发现为 MTA1 在 PTEN 的转录抑制中提供了一种机制作用，导致相关信号通路的调制。
