Data from Metastasis-Associated Protein 1 and Its Short Form Variant Stimulates <i>Wnt1</i> Transcription through Promoting Its Derepression from <i>Six3</i> Corepressor

Abstract

<div>Abstract<p>Although Wnt1 downstream signaling components have been well studied and activated in human cancer, the pathways that regulate <i>Wnt1</i> itself have not been explored in depth. Here, we provide gain-of-function, loss-of function, and molecular evidence supporting functional interactions between metastasis-associated protein 1 short-form (MTA1s), metastasis-associated protein 1 (MTA1), and Wnt1 signaling components during mammary gland development and tumorigenesis. Using multiple model systems involving overexpression or knockdown of MTA1s or MTA1, we discovered that MTA1s and MTA1 hyperactivate the Wnt1 pathway due to increased expression of <i>Wnt1</i> transcription. MTA1s and MTA1 physically interact with <i>Six3</i> chromatin, a protein product of which is a direct histone deacetylase inhibitor–dependent repressor of <i>Wnt1</i> transcription. Deletion of the MTA1s and MTA1 allele in murine embryonic fibroblasts resulted in the upregulation of Six3 and downregulation of Wnt signaling. In addition, mammary glands from the MTA1s/MTA1<sup>−/−</sup> mice exhibited increased recruitment of Six3 corepressor complex to the <i>Wnt1</i> promoter and inhibition of Wnt1 pathway in mammary glands. These findings identify MTA1s and MTA1 as important upstream modifiers of the <i>Wnt1</i> transcription, and consequently its functions, by directly inhibiting the transcription of <i>Six3</i>, allowing derepression of <i>Wnt1</i> transcription. Cancer Res; 70(16); 6649–58. ©2010 AACR.</p></div>