Akt Mediates Metastasis-Associated Gene 1 (MTA1) Regulating the Expression of E-cadherin and Promoting the Invasiveness of Prostate Cancer Cells

Abstract

Human metastasis-associated gene 1 (MTA1) is highly associated with the metastasis of prostate cancer; however, the molecular functions of MTA1 that facilitate metastasis remain unclear. In this study, we demonstrate that the silencing of MTA1 by siRNA treatment results in the upregulation of E-cadherin expression by the phosphorylation of AKT (p-AKT) and decreases the invasiveness of prostate cancer cells. We show that MTA1 is expressed in over 90% of prostate cancer tissues, especially metastatic prostate cancer tissue, comparing to non-expression in normal prostate tissue. RT-PCR analysis and Western blot assay showed that MTA1 expression is significantly higher in highly metastatic prostate cancer PC-3M-1E8 cells (1E8) than in poorly metastatic prostate cancer PC-3M-2B4 cells (2B4). Silencing MTA1 expression by siRNA treatment in 1E8 cells increased the cellular malignant characters, including the cellular adhesive ability, decreased the cellular invasive ability and changed the polarity of cellular cytoskeleton. 1E8 cells over-expressing MTA1 had a reduced expression of E-cadherin, while 1E8 cells treated with MTA1 siRNA had a higher expression of E-cadherin. The expression of phosphorylated AKT (p-AKT) or the inhibition of p-AKT by wortmannin treatment (100 nM) significantly altered the function of MTA1 in the regulation of E-cadherin expression. Alterations in E-cadherin expression changed the role of p-AKT in cellular malignant characters. All of these results demonstrate that MTA1 plays an important role in controlling the malignant transformation of prostate cancer cells through the p-AKT/E-cadherin pathway. This study also provides a new mechanistic role for MTA1 in the regulation of prostate cancer metastasis.

Down-Regulation of MiR-30c Promotes the Invasion of Non-Small Cell Lung Cancer by Targeting MTA1

“…However, the mechanism of miR-30c requires further research. MTA1 was an integral component of NuRD complex, and played an important role in invasive, as the same result of our study [29,30]. Overexpression of MTA1 was reported in carcinogenesis in human colorectal, breast, and lung cancers; it was a prognostic indicator and was associated with poor survival in esophageal, breast, and urinary cancers [31].…”

MTA1‐activated Epi‐microRNA‐22 regulates E‐cadherin and prostate cancer invasiveness

“…We have reported the functional importance of MTA1 in prostate cancer progression in both in vitro and in vivo studies . One of the proinvasive and prometastatic pathways regulated by MTA1 is regulation of E‐cadherin . In addition, our ChIP‐Seq studies identified Epi‐miRNAs directly regulated by MTA1 (A. Kumar, S. Dhar and A. S. Levenson, unpublished data).…”

DNA methylation of E-cadherin is a priming mechanism for prostate development

“…Regulators of CDH1 expression have been identified in developing tissues, including growth factors like TGF-β and FGF, transcriptional repressors such as Snail and Slug and other signaling pathways like NOTCH and WNT (Carraro et al, 2010; Herfs et al, 2008; Jamora et al, 2003; Jamora et al, 2005; Sirour et al, 2011; Wang et al, 2012). These same pathways regulate Cdh1 in epithelial cancers, as do other regulators.…”