The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications.

MTA (metastasis-associated gene) is a newly discovered family of cancer progression-related genes and their encoded products. MTA1, the first gene found in this family, has been repeatedly reported to be overexpressed along with its protein product MTA1 in a wide range of human cancers. In addition, the expression of MTA1/MTA1 correlates with the clinicopathological properties (malignant properties) of human cancers. MTA proteins are transcriptional co-repressors that function in histone deacetylation and are involved in the NuRD complex, which contains nucleosome remodeling and histone deacetylating molecules. MTA1 expression correlates with tumor formation in the mammary gland. In addition, MTA1 converts breast cancer cells to a more aggressive phenotype by repression of the estrogen receptor (ER) alpha trans-activation function through deacetylation of the chromatin in the ER-responsive element of ER-responsive genes. Furthermore, MTA1 plays an essential role in c-MYC-mediated cell transformation. Another member of this family, MTA3, is induced by estrogen and represses the expression of the transcriptional repressor Snail, a master regulator of "epithelial to mesenchymal transitions", resulting in the expression of the cell adhesion molecule E-cadherin and maintenance of a differentiated, normal epithelial phenotype in breast cells. In addition, tumor suppressor p53 protein is deacetylated and inactivated by both MTA1 and MTA2, leading to inhibition of growth arrest and apoptosis. Moreover, a hypoxia-inducible factor-1alpha (HIF-1alpha) is also deacetylated and stabilized by MTA1, resulting in angiogenesis. Thus, MTA proteins, especially MTA1, represent a possible set of master co-regulatory molecules involved in the carcinogenesis and progression of various malignant tumors. MTA proteins are proposed to be important new tools for clinical application in cancer diagnosis and treatment.