GATA zinc finger protein p66ß promotes breast cancer cell migration by acting as a co-activator of Snail.

The transcriptional repressor Snail induces EMT during embryonic development and tumor metastasis. Growing evidence indicates that Snail functions as a trans-activator to induce gene expression; however, the underlying mechanism remains elusive. Here, we report that Snail cooperates with GATA zinc finger protein p66ß to transactivate genes in breast cancer cells. Biologically, depletion of p66ß reduces cell migration and lung metastasis in BALB/c mice. Mechanistically, Snail interacts with p66ß and cooperatively induces gene transcription. Notably, a group of genes induced by Snail harbor conserved G-rich cis-elements (5'-GGGAGG-3', designated as G-box) in their proximal promoter regions. Snail directly binds to G-box via its zinc fingers and transactivates the G-box-containing promoters. p66ß enhances Snail binding affinity to G-box, whereas depletion of p66ß results in a decreased binding affinity of Snail to the endogenous promoters and concomitantly reduces the transcription of Snail-induced genes. Taken together, these data demonstrated that p66ß is critical for Snail-mediated cell migration by acting as a co-activator of Snail to induce genes containing G-box elements in the promoters.

CHST2-mediated sulfation of MECA79 antigens is critical for breast cancer cell migration and metastasis.

Snail is a denoted transcriptional repressor that plays key roles in epithelial-mesenchymal transition (EMT) and metastasis. Lately, a plethora of genes can be induced by stable expression of Snail in multiple cell lines. However, the biological roles of these upregulated genes are largely elusive. Here, we report identification of a gene encoding the key GlcNAc sulfation enzyme CHST2 is induced by Snail in multiple breast cancer cells. Biologically, CHST2 depletion results in inhibition of breast cancer cell migration and metastasis, while overexpression of CHST2 promotes cell migration and lung metastasis in nude mice. In addition, the expression level of MECA79 antigen is elevated and blocking the cell surface MECA79 antigen with specific antibodies can override cell migration mediated by CHST2 upregulation. Moreover, the sulfation inhibitor sodium chlorate effectively inhibits the cell migration induced by CHST2. Collectively, these data provide novel insights into the biology of Snail/CHST2/MECA79 axis in breast cancer progression and metastasis as well as potential therapeutic strategy for the diagnosis and treatment of breast cancer metastasis.