Steroid sulfatase deficiency causes cellular senescence and abnormal differentiation by inducing Yippee-like 3 expression in human keratinocytes

Human steroid sulfatase (STS) is an enzyme that catalyzes the hydrolysis of dehydroepiandrosterone sulfate (DHEAS), estrone sulfate (E1S), and cholesterol sulfate. Abnormal expression of STS causes several diseases including colorectal, breast, and prostate cancer and refractory skin disease. In particular, accumulation of intracellular cholesterol sulfate by STS deficiency leads to a skin disorder with abnormal keratinization called X-linked ichthyosis (XLI). To determine the detailed mechanisms of XLI, we performed RNA sequencing (RNA-seq) analysis using human keratinocyte HaCaT cells treated with cholesterol and cholesterol sulfate. Of the genes with expression changes greater than 1.5-fold, Yippee-like 3 (YPEL3), a factor expected to affect cell differentiation, was found. Induction of YPEL3 causes permanent growth arrest, cellular senescence, and inhibition of metastasis in normal and tumor cells. In this study, we demonstrate that YPEL3 expression was induced by STS deficiency and, using the CRISPR/Cas9 system, a partial knock-out (STS+/−) cell line was constructed to establish a disease model for XLI studies. Furthermore, we show that increased expression of YPEL3 in STS-deficient cell lines promoted cellular senescence and expression of keratinization-related proteins such as involucrin and loricrin. Our results suggest that upregulation of YPEL3 expression by STS deficiency may play a crucial role in inducing cellular senescence and abnormal differentiation in human keratinocytes.

Simultaneous expression of steroid sulfatase and androgen receptor reduced overall survival of patients with epithelial ovarian tumors

Background Ovarian cancer is usually diagnosed at an advanced stage due to its early asymptomatic course and late-stage non-specific symptoms. This highlights the importance of researching the molecular mechanisms involved in ovarian carcinogenesis as well as the discovery of novel prognostic markers that could help improve the survival outcome of patients. The aim of this study was to evaluate the expression of the steroid sulfatase (STS) in 154 samples of primary ovarian tumors. This protein is crucial in the intracellular conversion of sulfated steroid hormones to active steroid hormones. The presence of STS, 3β-HSD, and 17β-HSD1 result in the production of testosterone which act through the androgen receptor (AR) in the tumor cell. The presence of STS and AR in epithelial ovarian tumors and their association to the overall survival of patients was evaluated using Kaplan–Meier and Cox regression analyses. Results Immunoreactivity for STS was detected in 65% of the tumors and no association was observed with histological subtypes and clinical stages of the tumor. The STS expression in the tumors exhibiting immunoreactive AR resulted in a reduced survival (log-rank test, p = 0.032) and a risk factor in univariate and multivariate analysis, HR = 3.46, CI95% 1.00–11.92, p = 0.049 and HR = 5.92, CI95% 1.34–26.09, p = 0.019, respectively. Conclusions These findings suggest that the intracellular synthesis of testosterone acting through its receptor can promote tumor growth and progression. Moreover, the simultaneous expression of STS and AR constitutes an independent predictor of poor prognosis in epithelial ovarian tumors.

Anti-breast cancer potential of natural and synthetic coumarin derivatives

: Breast cancer is the most frequent female cancer and one of the leading causes of cancer death in women. There are many chemotherapy agents available for the treatment of breast cancer, but the current therapeutic options have not fulfilled the desired outcomes especially for the drug-resistant breast cancer therapy. Thus, there is an urgent need to develop novel anti-breast cancer agents. Coumarin is ubiquitous in natural and synthetic bioactive compounds, and coumarin derivatives are readily interacting with a variety of enzymes and receptors in breast cancer cells. Moreover, the coumarin-based Irosustat as the first-generation steroid sulfatase inhibitor in breast cancer is under clinical evaluations, revealing the potential of coumarin derivatives as novel anti-breast cancer agents. This review aims to describe the recent development of natural and synthetic coumarin derivatives with anti-breast cancer potential, covering the articles published from 2015 to 2020.

Chronic Exposure to 4-Nonylphenol Alters UDP-Glycosyltransferase and Sulfotransferase Clearance of Steroids in the Hard Coral, Pocillopora damicornis

The effects of the xenoestrogen 4-nonylphenol (4NP) on endocrine and metabolic homeostasis in the reef building coral, Pocillopora damicornis were investigated. The aim was to understand if ubiquitous nonylphenol ethoxylate contaminants in the marine environment result in altered homeostatic function. Coral colonies were chronically exposed (6 weeks) to a sublethal concentration (1 ppb) of 4NP and sampled over the coral’s lunar reproductive cycle. Although activity of steroidogenic enzymes [cytochrome P450 (CYP) 17, CYP 19, and 3-β-Hydroxysteroid dehydrogenase] and the conjugation enzyme glutathione-S-transferase was not altered, significant increases in the activity of the steroid clearing enzyme UDP-glycosyltransferase (UGT) were observed. The natural fluctuation of UGT activity with the lunar cycle was replaced with consistently high UGT activity throughout the reproductive cycle during 4NP exposure. No effect of 4NP on the reverse reaction, mediated by β-glucuronidase, was observed. Thus, 4NP shifts the UGT:β-glucuronidase ratio toward greater clearance at points in the lunar cycle where retention of compounds is typically favored. Additionally, 4NP reduced activity of the steroid regeneration enzyme steroid sulfatase, further shifting the system toward clearance rather than regeneration. These data imply that environmentally relevant levels of 4NP may be impacting the reproductive health of corals and threatening the persistence of coral reefs.

Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Aging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

Extremely preterm infant with persistent peeling skin: X-linked ichthyosis imitates prematurity

Objectives X-linked ichthyosis (XLI) is a genetic disorder caused by a deficiency in steroid sulfatase, an enzyme which catalyzes a reaction in estrone synthesis. The disorder primarily manifests as dry, scaly skin which may be difficult to diagnose in extremely preterm infants, as the dermatological features may be falsely attributed to a normal variant of skin for this population. Case presentation In this case report, we describe a male with XLI, born at 24 weeks gestation, who had persistent dry, flaky and hyperpigmented skin. This case is notable for the age of diagnosis in an extremely premature infant; day of life 105. In addition, this infant experienced out of proportion bronchopulmonary symptoms that we postulate may be linked to the steroid sulfatase deficiency, as estrogen is a mediator of surfactant production. Conclusions This report underscores the need to potentially evaluate persistent dry, flaky skin in the preterm infant, as XLI may also impact long term neurodevelopmental outcomes.