Human steroid sulfatase induces Wnt/beta-catenin signaling and epithelial-mesenchymal transition by upregulating Twist1 and HIF-1 alpha in human prostate and cervical cancer cells

초록

Steroid sulfatase (STS) catalyzes the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate (DHEAS) to their unconjugated biologically active forms. Although STS is considered a therapeutic target for estrogen-dependent diseases, the cellular functions of STS remain unclear. We found that STS induces Wnt/M beta-catenin s Delete ignaling in PC-3 and HeLa cells. STS increases levels of beta-catenin, phospho-beta-catenin, and phospho-GSK3 beta. Enhanced translocation of beta-catenin to the nucleus by STS might activate transcription of target genes such as cyclin D1, c-myc, and MMP-7. STS knockdown by siRNA resulted in downregulation of Wnt/M beta-catenin signaling. beta-catenin/TCF-mediated transcription was also enhanced by STS. STS induced an epithelial-mesenchymal transition (EMT) as it reduced the levels of E-cadherin, whereas levels of mesenchymal markers such as N-cadherin and vimentin were enhanced. We found that STS induced Twist1 expression through HIF alpha activation as HIF-1 alpha knockdown significantly blocks the ability of STS to induce Twist1 transcription. Furthermore, DHEA, but not DHEAS is capable of inducing Twist1. Treatment with a STS inhibitor prevented STS-mediated Wnt/M beta-catenin signaling and Twist1 expression. Interestingly, cancer cell migration, invasion, and MMPs expression induced by STS were also inhibited by a STS inhibitor. Taken together, these results suggest that STS induces Wnt/M beta-catenin signaling and EMT by upregulating Twist1 and HIF-1 alpha. The ability of STS to induce the Wnt/M beta-catenin signaling and EMT has profound implications on estrogen-mediated carcinogenesis in human cancer cells.

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