The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

Abstract

Gynecological diseases such as endometriosis, adenomyosis and uterine fibroids, and gynecological cancers including endometrial cancer and ovarian cancer, affect a large proportion of women. These diseases are estrogen dependent, and their progression often depends on local estrogen formation. In peripheral tissues, estrogens can be formed from the inactive precursors dehydroepiandrosterone sulfate and estrone sulfate. Sulfatase and sulfotransferases have pivotal roles in these processes, where sulfatase hydrolyzes estrone sulfate to estrone, and dehydroepiandrosterone sulfate to dehydroepiandrosterone, and sulfotransferases catalyze the reverse reactions. Further activation of estrone to the most potent estrogen, estradiol, is catalyzed by 17-ketosteroid reductases, while estradiol can also be formed from dehydroepiandrosterone by the sequential actions of 3β-hydroxysteroid dehydrogenase-Δ4-isomerase, aromatase, and 17-ketosteroid reductase. This review introduces the sulfatase and sulfotransferase enzymes, in terms of their structures and reaction mechanisms, and the regulation and different transcripts of their genes, together with the importance of their currently known single nucleotide polymorphisms. Data on expression of sulfatase and sulfotransferases in gynecological diseases are also reviewed. There are often unchanged mRNA and protein levels in diseased tissue, with higher sulfatase activities in cancerous endometrium, ovarian cancer cell lines, and adenomyosis. This can be indicative of a disturbed balance between the sulfatase and sulfotransferases enzymes, defining the potential for sulfatase as a drug target for treatment of gynecological diseases. Finally, clinical trials with sulfatase inhibitors are discussed, where two inhibitors have already concluded phase II trials, although so far with no convincing clinical outcomes for patients with endometrial cancer and endometriosis.

Sulfation pathways from red to green

“…The two mothers with WT/R329X and WT/W462Cfs*3 reported clinical features consistent with a phenotype of polycystic ovary syndrome, specifically chronic anovulation requiring ovulation induction (159). These alleles are far more common in the general population than the compound-heterozygous cases and may contribute significantly to the patient cohort with reduced sulfation capacity and associated health risks (160). Mutations in sulfotransferase genes additionally underlie a number of clinical conditions.…”

Structural basis for catalysis at the membrane-water interface

“…X-linked ichthyosis, a disease characterized by the scaling of the skin, has been associated with STS gene deletion or the presence of non-functional point mutants [75]. Higher STS activity has been observed in gynecological diseases such as endometrial cancer and ovarian cancer [76]. …”

Genetics and pathophysiology of mammalian sulfate biology

“…Whilst there are numerous pathological features associated with the 43 genes, the following sections focus on predominant features, including neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. The potential involvement of several sulfate maintenance genes in cancer has also gained attention from the scientific community in recent years, and those findings have been reviewed elsewhere (Dawson et al, 2010a;Dawson, 2012;Daniels and Kadlubar, 2013;Rižner, 2016).…”