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

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.