Extracellular Acidosis Differentially Regulates Estrogen Receptor β-Dependent EMT Reprogramming in Female and Male Melanoma Cells

Clinical outcomes of melanoma patients pointed out a gender disparity that supports a correlation between sex hormone activity on estrogen receptors (ER) and melanoma development and progression. Here, we found that the epithelial-to-mesenchymal transition (EMT) of melanoma cells induced by extracellular acidosis, which is a crucial hallmark of solid cancers, correlates with the expression of ER beta, the most representative ER on melanoma cells. Extracellular acidosis induces an enhanced expression of ER beta in female cells and EMT markers remain unchanged, while extracellular acidosis did not induce the expression of ER beta in male cells and EMT was strongly promoted. An inverse relationship between ER beta expression and EMT markers in melanoma cells of different sex exposed to extracellular acidosis was revealed by two different technical approaches: florescence-activated cell sorting of high ER beta expressing cell subpopulations and ER beta receptor silencing. Finally, we found that ER beta regulates EMT through NF-kappa B activation. These results demonstrate that extracellular acidosis drives a differential ER beta regulation in male and female melanoma cells and that this gender disparity might open new perspectives for personalized therapeutic approaches.