Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor–Mediated Activation of Estrogen Sulfotransferase

Gong, Haibiao; Jarzynka, Michael J.; Cole, Timothy J.; Lee, Jung Hoon; Wada, Taira; Zhang, Bin; Gao, Jie; Song, Wen‐Chao; DeFranco, Donald B.; Cheng, Shi‐Yuan; Xie, Wen

doi:10.1158/0008-5472.can-08-1545

Cited by 131 publications

(131 citation statements)

References 54 publications

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“…Considering that estrogens and glucocorticoids often oppose each other to regulate cellular responses (44), the observed methylation of NR3C1 may reflect an analogous role of protein arginine methylation in glucocorticoid signaling as previously described for estrogen signaling (43). Additionally, we identified Insulin Receptor Substrates 2 & 4 (IRS2 and IRS4) to be modified by MMA, suggesting that arginine methylation may be involved in insulin signaling and glucose metabolism.…”

Section: Identification Of Endogenous Arginine Mono-methylation (Mma)supporting

confidence: 63%

Proteomic Analysis of Arginine Methylation Sites in Human Cells Reveals Dynamic Regulation During Transcriptional Arrest

Sylvestersen

Horn

Jungmichel

et al. 2014

Molecular & Cellular Proteomics

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The covalent attachment of methyl groups to the side-chain of arginine residues is known to play essential roles in regulation of transcription, protein function, and RNA metabolism. The specific N-methylation of arginine residues is catalyzed by a small family of gene products known as protein arginine methyltransferases; however, very little is known about which arginine residues become methylated on target substrates. Here we describe a proteomics methodology that combines single-step immunoenrichment of methylated peptides with high-resolution mass spectrometry to identify endogenous arginine mono-methylation (MMA) sites. We thereby identify 1027 site-specific MMA sites on 494 human proteins, discovering numerous novel mono-methylation targets and confirming the majority of currently known MMA substrates. Nuclear RNA-binding proteins involved in RNA processing, RNA localization, transcription, and chromatin remodeling are predominantly found modified with MMA. Despite this, MMA sites prominently are located outside RNA-binding domains as compared with the proteome-wide distribution of arginine residues. Quantification of arginine methylation in cells treated with Actinomycin D uncovers strong site-specific regulation of MMA sites during transcriptional arrest. Interestingly, several MMA sites are down-regulated after a few hours of transcriptional arrest. In contrast, the corresponding dimethylation or protein expression levels are not altered, confirming that MMA sites contain regulated functions on their own. Collectively, we present a site-specific MMA data set in human cells and demonstrate for the first time that MMA is a dynamic post-translational modification regulated during transcriptional arrest by a hitherto uncharacterized arginine demethylase. Molecular & Cellular Proteomics

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Section: Identification Of Endogenous Arginine Mono-methylation (Mma)supporting

confidence: 63%

Proteomic Analysis of Arginine Methylation Sites in Human Cells Reveals Dynamic Regulation During Transcriptional Arrest

Sylvestersen

Horn

Jungmichel

et al. 2014

Molecular & Cellular Proteomics

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“…[17][18][19] Therefore, it is important to examine the expression of GR and other steroid receptors in thymic tumors.…”

mentioning

confidence: 99%

Steroid receptor expression in thymomas and thymic carcinomas

Mimae

Tsuta

Takahashi

et al. 2011

Cancer

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BACKGROUND: Although protein expressions of glucocorticoid receptor (GR), estrogen receptors (ERa and ERb), progesterone receptor A (PgR-A), and androgen receptor (AR) were shown to play roles in the growth and differentiation of normal thymus and thymic tumors, to the authors' knowledge their association with patient characteristics and prognosis has yet to be determined. METHODS: A series of 140 thymic epithelial tumors (57 type A þ AB thymomas, 40 type B1 þ B2 thymomas, 6 type B3 thymomas, and 37 thymic carcinomas) were examined for GR, ERa, ERb, PgR-A, and AR expression using immunohistochemistry. In addition, the correlation between expression of these hormone receptors and clinicopathologic factors and overall survival (OS) was assessed. RESULTS: GR and ERb demonstrated a high rate of expression in thymomas and thymic carcinomas (82.9% and 76.4%, respectively), whereas rates of ERa, PgR-A, and AR expression were low (13.6%, 0.71%, and 23.6%, respectively). A significant correlation (P < .05) was found between ERa expression and tumor size and between ERb expression and tumor stage. Multivariate analyses revealed that histologic subtype (P ¼ .0039), tumor stage (P ¼ .0012), and GR expression (P ¼ .0025) were significantly correlated with the 10-year OS rate. CONCLUSIONS: GR and ERb demonstrated high rates of expression in thymomas and thymic carcinomas. Furthermore, multivariate analysis revealed that GR expression was associated with better prognosis in patients with surgically resected thymomas and thymic carcinomas. Cancer 2011;117:4396-

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“…In the current study, we tried to determine the free E2 plasma concentration using the same ELISA kit, but the concentration was too low to be detectable, indicating the plasma E2 concentration is much lower, which is in agreement with the previous results. Additionally, because stronger uterine estrogen responses are indicative of higher levels of active estrogens and vice versa [17,46] , uterine estrogen responses are usually used to indirectly evaluate the overall level of active estrogens in the body. In this study, TM208 significantly inhibited the uterine responses because the uterine volume and weight obviously decreased after treatment with TM208 ( Figure 6B), indicating that TM208 reduced the levels of circulating estrogen.…”

Section: Discussionmentioning

confidence: 99%

“…Gong et al reported that the activation of EST is mediated by both the glucocorticoid receptor (GR) and orphan nuclear receptor liver X receptor (LXR), leading to estrogen deprivation and the inhibition of breast tumor growth in vivo [17,46] . Furthermore, these responses were not observed in EST knockout mice after treatment with LXR agonists.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, targeted activation of EST is likely to pave an alternative route for success in hormone-dependent breast cancer treatment. Some groups have applied the upregulation of EST by genetic methods [17,18] or through the administration of progestins [19] to treat breast cancer. Some commonly used anticancer drugs (such as Tam) [20] and methotrexate [21] and some natural flavonoid compounds (such as biochanin A and genistein) [22] that have been shown to possess potential anti-breast cancer properties have been found to significantly induce rSULT1A1 and rSULT2A1 in the livers of normal rats.…”

Section: Introductionmentioning

confidence: 99%

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Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208

Chen

Song

et al. 2015

Acta Pharmacol Sin

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Aim: Sulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo. Methods: The viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg·kg -1 ·d -1 ) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses. Results: Treatment with TM208 (10, 15 and 20 µmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo. Conclusion: The induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.

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Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor–Mediated Activation of Estrogen Sulfotransferase

Cited by 131 publications

References 54 publications

Proteomic Analysis of Arginine Methylation Sites in Human Cells Reveals Dynamic Regulation During Transcriptional Arrest

Proteomic Analysis of Arginine Methylation Sites in Human Cells Reveals Dynamic Regulation During Transcriptional Arrest

Steroid receptor expression in thymomas and thymic carcinomas

Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208

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