The androgen receptor inhibits transcription of GPER1 by preventing Sp1 and Sp3 from binding to the promoters in prostate cancer cells

McDermott, Austin; Kim, Kyounghyun; Kasper, Susan; Ho, Shuk‐Mei; Leung, Yuet-Kin

doi:10.18632/oncotarget.28169

Cited by 3 publications

(3 citation statements)

References 72 publications

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“…We next investigated the molecular network underlying GPER1 activation in MM. Previous studies indicated the presence, in the GPER1 promoter, of binding sites for Sp1 [ 36 ], an oncogenic transcription factor highly expressed in MM [ 37 ]. To confirm Sp1 binding to GPER1 promoter in MM cells, we carried out a ChIP assay using Sp1 antibodies in the presence of G-1 or a vehicle, which confirmed the binding of Sp1 to GPER promoter, conversely reduced after G-1 treatment ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma

Gallo Cantafio,

Torcasio,

Scionti

et al. 2023

Cells

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G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we show that GPER1 mRNA is down-regulated in plasma cells from overt multiple myeloma (MM) and plasma cell leukemia patients as compared to normal donors or pre-malignant conditions (monoclonal gammopathy of undetermined significance and smoldering MM); moreover, lower GPER1 expression associates with worse overall survival of MM patients. Using the clinically applicable GPER1-selective agonist G-1, we demonstrate that the pharmacological activation of GPER1 triggered in vitro anti-MM activity through apoptosis induction, also overcoming the protective effects exerted by bone marrow stromal cells. Noteworthy, G-1 treatment reduced in vivo MM growth in two distinct xenograft models, even bearing bortezomib-resistant MM cells. Mechanistically, G-1 upregulated the miR-29b oncosuppressive network, blunting an established miR-29b-Sp1 feedback loop operative in MM cells. Overall, this study highlights the druggability of GPER1 in MM, providing the first preclinical framework for further development of GPER1 agonists to treat this malignancy.

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Section: Resultsmentioning

confidence: 99%

GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma

Gallo Cantafio,

Torcasio,

Scionti

et al. 2023

Cells

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“…The relationship between glucocorticoids such as dexamethasone and estrogen receptor signaling is less clear, with most studies showing an ability of DEX to inhibit downstream signaling without direct effects on receptor expression [ 36 , 37 ]. Previous work in prostate cancer cells similarly showed DHT-induced suppression of GPER that occurs through androgen receptor binding to transcription factors Sp1 and Sp3 and prevent their transcription of GPER [ 38 , 39 ]. Reciprocal interference between the gene transcription outputs for estrogen versus androgen is also demonstrated in breast cancer [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Dihydrotestosterone induces arterial stiffening in female mice

Horton,

Wilkinson,

Kilanowski-Doroh

et al. 2024

Biol Sex Differ

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Background Androgens are important sex hormones in both men and women and are supplemented when endogenous levels are low, for gender transitioning, or to increase libido. Androgens also circulate at higher levels in women with polycystic ovarian syndrome, a condition that increases the risk for cardiovascular diseases including hypertension and arterial stiffness. Since our previous work shows an important role for the G protein-coupled estrogen receptor (GPER) in arterial stiffness, we hypothesized that other hormones including androgens may impact arterial stiffness in female mice via downregulation of GPER. Methods The impact of the non-aromatizable androgen dihydrotestosterone (DHT), the glucocorticoid dexamethasone, and the progestin medroxyprogesterone acetate (all 100 nM for 24 h) on GPER and ERα expression was assessed in cultured vascular smooth muscle cells using droplet digital PCR (ddPCR). To assess the in vivo impact of the DHT-induced downregulation of GPER, female ovary-intact C57Bl/6 mice at 15–16 weeks of age were treated with silastic capsules containing DHT for 4 weeks, one with a dosage expected to mimic human male DHT levels and another to double the expected human concentration (n = 8–9/group). Results In cultured vascular smooth muscle cells, GPER mRNA was decreased by DHT (P = 0.001) but was not impacted by dexamethasone or medroxyprogesterone. In contrast, ERα expression in cultured cells was significantly suppressed by all three hormones (P < 0.0001). In control mice or mice treated with a single or double dose of DHT, a dose-dependent increase in body weight was observed (control 22 ± 2 g, single dose 24 ± 2 g, double dose 26 ± 2 g; P = 0.0002). Intracarotid stiffness measured via pulse wave velocity showed a more than two-fold increase in both DHT-treated groups (control 1.9 ± 0.3 m/s, single dose 4.3 ± 0.8 m/s, double dose 4.8 ± 1.0 m/s). This increase in arterial stiffness occurred independent of changes in blood pressure (P = 0.59). Histological analysis of aortic sections using Masson’s trichrome showed a significant decrease in collagen between the control group (24 ± 5%) and the double dose group (17 ± 3%, P = 0.007), despite no changes in aortic wall thickness or smooth muscle content. Lastly, ddPCR showed that in vivo DHT treatment decreased aortic expression of both GPER (control 20 ± 5, single dose 10.5 ± 5.6, double dose 10 ± 4 copies/ng; P = 0.001) and ERα (control 54 ± 2, single dose 24 ± 13, and double dose 23 ± 12 copies/ng; P = 0.003). Conclusions These findings indicate that androgen promotes arterial stiffening and cardiovascular damage in female mice and is associated with decreased estrogen receptor expression. These data are important for transgender men, women using testosterone for fitness or reduced libido, as well as patients with polycystic ovarian syndrome.

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“…The relationship between glucocorticoids such as dexamethasone and estrogen receptor signaling is less clear, with most studies showing an ability of DEX to inhibit downstream signaling without direct effects on receptor expression [22,23]. Previous work in prostate cancer cells similarly showed DHT-induced suppression of GPER that occurs through androgen receptor binding to transcription factors Sp1 and Sp3 and prevent their transcription of GPER [24,25]. This decrease in receptor mRNA most likely lessens the beneficial effects of estrogen on cardiovascular function.…”

Section: Discussionmentioning

confidence: 99%

Dihydrotestosterone Induces Arterial Stiffening in Female Mice

Horton

Wilkinson

Kilanowski‐Doroh

et al. 2023

Preprint

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Background: Testosterone is the predominant sex hormone in men and is increased in women with polycystic ovarian syndrome. These patients also experience an increased risk for cardiovascular diseases including hypertension and arterial stiffness. Since our previous work shows an important role for the G protein-coupled estrogen receptor (GPER) in arterial stiffness, we hypothesized that other hormones including androgens may impact arterial stiffness in female mice via regulation of GPER. Methods: The impact of the non-aromatizable androgen dihydrotestosterone (DHT), the glucocorticoid dexamethasone, and the progestin medroxyprogesterone acetate (all 100 nM for 24 h) on GPER and ERα expression was assessed in cultured vascular smooth muscle cells using droplet digital PCR (ddPCR). To assess the in vivo impact of the DHT-induced downregulation of GPER, female ovary-intact C57Bl/6 mice were treated with silastic capsules containing DHT for 4 weeks, one with a dosage expected to mimic human male DHT levels and another to double the expected human concentration (n=8-9/group). Results: GPER mRNA was only decreased by DHT (P=0.001), while ERα expression was significantly suppressed by all hormones (P<0.0001). While blood pressure was not different between groups (P= 0.59), there was a dose-dependent increase in body weight (control 22±2 g, single dose 24±2 g, double dose 26±2 g; P=0.0002). Intracarotid stiffness measured via pulse wave velocity showed a more than two-fold increase in both DHT-treated groups (control 1.9±0.3 m/s, single dose 4.3±0.8 m/s, double dose 4.8±1.0 m/s). Histological analysis of aortic sections using Masson’s trichrome showed a significant decrease in collagen between the control group (24 ± 5%) and the double dose group (17 ± 3%, P=0.007), despite no changes in aortic wall thickness or smooth muscle content. Lastly, ddPCR showed that in vivo DHT treatment decreased aortic expression of both GPER (control 20±5, single dose 10.5 ± 5.6, double dose 10±4 copies/ng; P=0.001) and ERα (control 54±2, single dose 24±13, and double dose 23 ± 12 copies/ng; P=0.003). Conclusions: These findings indicate that testosterone promotes arterial stiffening and cardiovascular damage in female mice and is associated with decreased estrogen receptor expression. These data are important not only for polycystic ovarian syndrome patients but also women using testosterone for fitness, gender transitioning, or reduced libido.

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The androgen receptor inhibits transcription of GPER1 by preventing Sp1 and Sp3 from binding to the promoters in prostate cancer cells

Cited by 3 publications

References 72 publications

GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma

GPER1 Activation Exerts Anti-Tumor Activity in Multiple Myeloma

Dihydrotestosterone induces arterial stiffening in female mice

Dihydrotestosterone Induces Arterial Stiffening in Female Mice

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