MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines.

Metastasis is a complex process facilitated by the action of several genes. Metastasis associated 1 (MTA1) gene is one such gene which assists the process of metastasis by regulating several molecular targets. MTA1 acts as part of a nucleosome remodelling and histone deacetylation complex, which is involved in transcriptional regulation. Expression of MTA1 has been shown to be closely correlated with aggressiveness in several types of cancers, including breast cancer. In the present study we show that MTA1 regulates SMAD7, a component of Transforming growth factor beta (TGFbeta) signalling. TGFbeta signals are transduced to the nucleus by the Smad family of proteins, which includes Smad7, an inhibitory SMAD, which acts as a negative regulator of TGFbeta. On knockdown of MTA1, SMAD7 expression increases. Treating cells with a histone deacetylase inhibitor also increases SMAD7 expression. MTA1 is recruited to SMAD7 promoter region. SMAD7 inhibits activation of SMAD2 and SMAD3 and we show that the levels of these active SMAD proteins are decreased in cells expressing shRNA against MTA1. We further show that on MTA1 knockdown, the expression of downstream targets of SMAD7 is decreased. MTA1 thus appears to regulate a key inhibitor of TGFbeta signalling, SMAD7. By regulating molecules like SMAD7 MTA1 might assist the process of tumourigenesis and metastasis.