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

Abstract

// Sangyun Shin 1, * , Hee-Jung Im 1, * , Yeo-Jung Kwon 1, * , Dong-Jin Ye 1 , Hyoung-Seok Baek 1 , Donghak Kim 2 , Hyung-Kyoon Choi 1 and Young-Jin Chun 1 1 College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea 2 Department of Biological Sciences, Konkuk University, Seoul 05029, Republic of Korea * These authors have contributed equally to this work Correspondence to: Young-Jin Chun, email: yjchun@cau.ac.kr Keywords: steroid sulfatase, epithelial-mesenchymal transition, Wnt/β–catenin pathway, HIF-1α, Twist1 Received: March 06, 2017      Accepted: May 22, 2017      Published: June 27, 2017 ABSTRACT 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/β-catenin s Delete ignaling in PC-3 and HeLa cells. STS increases levels of β-catenin, phospho-β-catenin, and phospho-GSK3β. Enhanced translocation of β-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/β-catenin signaling. β-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 HIFα activation as HIF-1α 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/β-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/β-catenin signaling and EMT by upregulating Twist1 and HIF-1α. The ability of STS to induce the Wnt/β-catenin signaling and EMT has profound implications on estrogen-mediated carcinogenesis in human cancer cells.