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

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.

MiR-200c-3p inhibits cell migration and invasion of clear cell renal cell carcinoma via regulating SLC6A1

“…For example, EMT was induced by SET in pancreatic cancer, lung cancer, 32 prostatic carcinoma and cervical cancer. 33 As for CCRCC, it was revealed that EMT was attenuated by miR-138 in CCRCC cells, indicating the tumor suppression function of miR-138. 34 on the contrary, IL-6 induces EMT and stimulates metastasis in CCRCC.…”

High expression of SLCO2B1 is associated with prostate cancer recurrence after radical prostatectomy

“…Considering these previous reports and our GSEA results, high expression of SLCO2B1 appears to activate EMT through the upregulation of sonic hedgehog, IL-6/JAK/STAT3 and K-ras signaling pathways. In agreement, DHEA, one of the major metabolites from DHEAS, has been shown to accelerate EMT through E-cadherin suppression and the induction of N-cadherin and Vimentin in PCa [ 34 ]. Taken together, it is possible that high expression of SLCO2B1 accelerates the influx of DHEAS, which is then metabolized to the more active DHEA.…”

SULFATION PATHWAYS: Insights into steroid sulfation and desulfation pathways

“…These actions were shown to be through increased estrogen desulfation and activation of the GPER, a finding further supported by evidence these effects may be modulated by a hypoxic environment (Bustos et al 2017). Indeed, it is of interest to note STS activity can increase hypoxia inducible factor HIF1A expression in cervical and prostate cancer cells, suggesting STS action may be further regulated by hypoxic conditions (Shin et al 2017). Furthermore, E 2 treatment increases both STS activity (Gilligan et al 2017a) and GPER expression in CRC (Bustos et al 2017), suggesting a novel positive feedback loop through which E 2 can drive CRC proliferation.…”