Downregulation of estrogen-related receptor alpha inhibits human cutaneous squamous cell carcinoma cell proliferation and migration by regulating EMT via fibronectin and STAT3 signaling pathways

Estrogen-related receptor alpha (ERR alpha), one of orphan nuclear receptors, has been recently revealed as an oncogenic regulator in a variety of cancers. However, the linking gain of ERR alpha expression and cancer progression in cutaneous squamous cell carcinoma (cSCC) is largely unknown. Here, we showed that the mRNA and protein expression levels of ERR alpha were markedly higher in A431 cells compared with human keratinocyte cell line HaCaT, and targeted inhibition of ERR alpha by shRNA or its inverse agonist XCT790 significantly suppressed A431 cells proliferation and migration, while overexpression of ERR alpha promoted cell proliferation and migration. In addition, the data revealed that ERR alpha downregulation markedly inhibited the epithelial mesenchymal transition (EMT) of A431 cells with increasing the expression of E-cadherin and decreasing fibronectin (FN) and vimentin. Results from further experiments using Western blot suggested that ERR alpha suppression inhibited signal transducer and activator of transcription (STAT3) protein expression. In contrast, overexpression of ERR alpha promoted EMT and the activation of STAT3 pathway. Moreover, treatment with specific STAT3 inhibitor reversed EMT markers in ERR alpha-overexpressing A431 cells. In tumor xenografts of A431 cells, we further showed that ERR alpha depletion inhibited cSCC tumor growth in vivo. Taken together, these results demonstrate, for the first time, that ERR alpha may function as an oncoprotein in cSCC to accelerate tumor aggressiveness by promoting EMT via FN and STAT3 pathway, and it could be a novel target for cSCC therapy.