Galectin-3 contributes to melanoma growth and metastasis via regulation of NFAT1 and autotaxin

Melanoma is the deadliest form of skin Cancer in which patients with metastatic disease have a 5-year survival rate of less than 10%. Recently, the overexpression of a β-galactoside binding protein, Galectin-3 (LGALS3), has been correlated with metastatic melanoma in patients. We have previously shown that silencing Galectin-3 in metastatic melanoma cells reduces tumor growth and metastasis. Gene expression profiling identified the protumorigenic gene Autotaxin (ENPP2) to be downregulated after silencing Galectin-3. Here we report that Galectin-3 regulates Autotaxin expression at the transcriptional level by modulating the expression of the transcription factor NFAT1 (NFATC2). Silencing Galectin-3 reduced NFAT1 protein expression, which resulted in decreased Autotaxin expression and activity. Reexpression of Autotaxin in Galectin-3 silenced melanoma cells rescues angiogenesis, tumor growth, and metastasis in vivo. Silencing NFAT1 expression in metastatic melanoma cells inhibited tumor growth and metastatic capabilities in vivo. Our data elucidate a previously unidentified mechanism by which Galectin-3 regulates Autotaxin and assign a novel role for NFAT1 during melanoma progression.