SULT2B1b Sulfotransferase: Induction by Vitamin D Receptor and Reduced Expression in Prostate Cancer

Abstract

An elevated tumor tissue androgen level, which reactivates androgen receptor in recurrent prostate cancer, arises from the intratumor synthesis of 5α-dihydrotestosterone through use of the precursor steroid dehydroepiandrosterone (DHEA) and is fueled by the steroidogenic enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD1), aldoketoreductase (AKR1C3), and steroid 5-alpha reductase, type 1 (SRD5A1) present in cancer tissue. Sulfotransferase 2B1b (SULT2B1b) (in short, SULT2B) is a prostate-expressed hydroxysteroid SULT that converts cholesterol, oxysterols, and DHEA to 3β-sulfates. DHEA metabolism involving sulfonation by SULT2B can potentially interfere with intraprostate androgen synthesis due to reduction of free DHEA pool and, thus, conversion of DHEA to androstenedione. Here we report that in prostatectomy specimens from treatment-naive patients, SULT2B expression is markedly reduced in malignant tissue (P < .001, Mann-Whitney U test) compared with robust expression in adjacent nonmalignant glands. SULT2B was detected in formalin-fixed specimens by immunohistochemistry on individual sections and tissue array. Immunoblotting of protein lysates of frozen cancer and matched benign tissue confirmed immunohistochemistry results. An in-house-developed rabbit polyclonal antibody against full-length human SULT2B was validated for specificity and used in the analyses. Ligand-activated vitamin D receptor induced the SULT2B1 promoter in vivo in mouse prostate and increased SULT2B mRNA and protein levels in vitro in prostate cancer cells. A vitamin D receptor/retinoid X receptor-α-bound DNA element (with a DR7 motif) mediated induction of the transfected SULT2B1 promoter in calcitriol-treated cells. SULT2B knockdown caused an increased proliferation rate of prostate cancer cells upon stimulation by DHEA. These results suggest that the tumor tissue SULT2B level may partly control prostate cancer growth, and its induction in a therapeutic setting may inhibit disease progression.

Cholesterol Sulfonation Enzyme, SULT2B1b, Modulates AR and Cell Growth Properties in Prostate Cancer

“…In contrast to our findings, two groups independently reported that SULT2B1b KD promotes LNCaP cell growth while maintained in androgen-depleted conditions with DHEA supplementation(19,21). Although we do not fully understand the reason(s) for this discrepancy, culture medium conditions in growth assays may play a role.…”

“…DHEA) leading to decreased AR-dependent proliferative signaling, data herein directly show that SULT2B1b activity is positively correlated to AR activity, which implies an alternative mechanism of AR regulation is occurring. While our studies in cell lines support our previous findings that CS accumulates in precancerous and cancerous prostate tissues compared to normal counterparts, we also found that a single benign cell line, RWPE-1, has robust SULT2B1b expression and activity, which likely reflects the heterogeneity of SULT2B1b expression/activity within prostate tissue as has been reported by others(19). In contrast to the findings of Seo et al(19), recent evidence in cancer cells suggest SULT2B1b plays a role in cancer growth/aggressiveness.…”

“…SULT2B1b was studied in PCa in androgen-free conditions supplemented with DHEA(19,21). However, SULT2B1b has not been previously evaluated in androgen-replete conditions that mimic normal biology and PCa progression, consistent with the conditions in which CS accumulation was observed(10).…”

Overexpression of SULT2B1b Promotes Angiogenesis in Human Gastric Cancer

“…To date, there are evidences linking SULT2B1b gene to tumor growth of colorectal, hepatocellular and prostate carcinoma [14][15][16]. However, the reported effects of SULT2B1b on tumor biology are conflicting.…”

“…Hu et al [14] provided the evidence that overexpression of SULT2B1b promoted cell growth and invasion in colorectal carcinoma. Yang et al [16] showed that overexpression of SULT2B1b promoted the proliferation of human hepatocarcinoma cells, whereas Seo et al [15] demonstrated that the expression of SULT2B1b was decreased in prostate cancer and depletion of SULT2B1b resulted in increased proliferation rate of prostate cancer cells. These conflicting results indicate that the role of SULT2B1b in different cancers is varies with the type of cancer.…”