Effect of 25(OH)D on the gene expression of breast cancer cell MDA-MB-453
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE247667 | GEO | 2024/05/15
REPOSITORIES: GEO
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Project description:Vitamin D is a pro-hormone that possesses various anticancer effects through diverse mechanisms. The enzyme vitamin D-25-hydroxylase can convert vitamin D into 25-hydroxyvitamin D (25(OH)D) in the liver. 25(OH)D serves as the precursor of 1,25-dihydroxyvitamin D (1,25(OH)2D or calcitriol), which can be transformed into 1,25(OH)2D by the enzyme CYP27B1. CYP27B1 is primarily distributed in the kidneys but can also be found in other tissues, such as the breast and colon. Although 1,25-dihydroxyvitamin D has been the primary object of in vitro studies, emerging evidence suggests that 25(OH)D can also generate anticancer effects by transforming into 1,25(OH)2D in the manner of autocrine and paracrine. Our study aims to investigate the impact of 25(OH)D on breast cancer and its effect on the expression of small RNA in breast cancer cells cultured with 100nM 25(OH)D.
2024-05-15 | GSE250048 | GEO
Project description:In this study, we compared the modulation of the transcriptome of human PBMCs by the vitamin D metabolites 25-hydroxyvitamin D3 (25(OH)D3), 25(OH)D2 and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3).
2022-06-21 | GSE199273 | GEO
Project description:Fibroblast growth factor 23 (FGF23) is produced and secreted by osteocytes and is essential for maintaining phosphate homeostasis. One of the main regulators of FGF23, 1,25-dihydroxyvitamin D (1,25(OH)2D3), is primarily synthesized in the kidney from 25-hydroxyvitamin D (25(OH)D) by 1α-hydroxylase (encoded by CYP27B1). Hitherto, it is unclear whether osteocytes can convert 25(OH)D and thereby allow for 1,25(OH)2D3 to induce FGF23 production and secretion locally. Here, we differentiated MC3T3-E1 cells towards osteocyte-like cells expressing and secreting FGF23. Treatment with 10-6 M 25(OH)D resulted in conversion of 25(OH)D to 150 pmol/L 1,25(OH)2D3 and increased FGF23 expression and secretion but the converted amount of 1,25(OH)2D3 was insufficient to trigger an FGF23 response, so the effect on FGF23 was most likely directly caused by 25(OH)D. Interestingly, combining phosphate with 25(OH)D resulted in a synergistic increase in FGF23 expression and secretion, likely due to activation of additional signaling pathways by phosphate. Blockage of the vitamin D receptor (VDR) only partially abolished the effects of 25(OH)D or 25(OH)D combined with phosphate on Fgf23, while completely inhibiting the upregulation of cytochrome P450 family 24 subfamily A member 1 (Cyp24a1), encoding for 24-hydroxylase. RNA sequencing and in silico analyses showed that this could potentially be mediated by the nuclear receptors Retinoic Acid Receptor b (RARB) and Estrogen Receptor 2 (ESR2). Taken together, we demonstrate that osteocytes are able to convert 25(OH)D to 1,25(OH)2D3, but this is insufficient for FGF23 activation, implicating a direct effect of 25(OH)D in the regulation of FGF23, which occurs at least partially independent from its cognate vitamin D receptor Moreover, phosphate and 25(OH)D synergistically increase expression and secretion of FGF23, which warrants investigating consequences in patients receiving a combination of vitamin D analogues and phosphate supplements. These observations help us to further understand the complex relations between, phosphate, vitamin D and FGF23.
2024-08-01 | GSE239761 | GEO
Project description:Heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC1/C2) functions as an RNA splicing regulator through co-transcriptional association with nascent mRNA. HnRNPC1/C2 can also bind to double-stranded DNA as a vitamin D response element-binding protein (VDRE-BP), thereby regulating transcriptional activity of the vitamin D receptor (VDR) bound to 1,25-dihydroxyvitamin D (1,25(OH)2D). In this way hnRNPC1/C2 may act as a coupling factor for 1,25(OH)2D-directed transcription and RNA splicing. Studies using MG63 osteoblastic cells confirmed that 1,25(OH)2D-VDR mediated induction of the gene for the enzyme 24-hydroxylase (CYP24A1), involved CYP24A1-specific chromatin and RNA immunoprecipitation of hnRNPC1/C2. Furthermore, small interfering (siRNA) knockdown of hnRNPC1/C2 in MG63 cells and was associated with dysregulated expression of CYP24A1 and an alternatively spliced form of CYP24A1 (CYP24A1-variant 2). Genome-wide analysis of RNA expression and alternative splicing indicated that dual role of hnRNPC1/C2 in directing 1,25(OH)2D-mediated gene expression is not restricted to the classical VDR-target CYP24A1. Knockdown of hnRNPC1/C2 resulted in 3500 differentially expressed genes (DEG), and treatment with 1,25(OH)2D 324 DEG. A further 87 DEG were only observed in 1,25(OH)2D-treated cells in hnRNPC1/C2 knockdown cells. HnRNPC1/C2 knockdown or 1,25(OH)2D treatment also induced alternative splicing (AS) (5039 and 310 AS events respectively). Combined hnRNPC1/C2 knockdown and 1,25(OH)2D treatment resulted in significant overlap between DEG and AS genes, but this was not observed for 1,25(OH)2D treatment alone. These data indicate that hnRNPC1/C2 can act to couple transcriptional and splicing responses to 1,25(OH)2D by binding to both DNA and RNA. Similar mechanisms may also exist for other members of the hnRNP and steroid receptor family.
2016-12-06 | GSE63086 | GEO
Project description:Human kidney was obtained from the University of Wisconsin Madison Organ Procurement Program from a deceased 69 year old female patient and the cortex was dissected from 3 different cortex locations. Associated publication abstract: Targeted genomic deletions identify diverse enhancer functions and generate a kidney-specific, endocrine-deficient Cyp27b1 pseudo-null mouse Vitamin D3 is terminally bioactivated in the kidney to 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) via cytochrome P450 family 27 subfamily B member 1 (CYP27B1), whose gene is regulated by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1,25(OH)2D3. Our recent genomic studies in the mouse have revealed a complex kidney-specific enhancer module within the introns of adjacent methyltransferase like 1 (Mettl1) and Mettl21b that mediate basal and PTH induced expression of Cyp27b1 and FGF23- and 1,25(OH)2D3-mediated repression. Gross deletion of these segments in mice has severe consequences on Cyp27b1 regulation and skeletal phenotype, but does not affect Cyp27b1 expression in non-renal target cells (NRTCs). Here, we report a bimodal activity in the Mettl1 intronic enhancer with components responsible for PTH-mediated Cyp27b1 induction and 1,25(OH)2D3-mediated repression and additional activities, including FGF23 repression, within the Mettl21b enhancers. Deletion of both submodules eliminated basal Cyp27b1 expression and regulation in the kidney, leading to systemic and skeletal phenotypes similar to those of Cyp27b1-null mice. However, basal expression and lipopolysaccharide-induced regulation of Cyp27b1 in NRTCs was unperturbed. Importantly, dietary normalization of calcium, phosphate, PTH, and FGF23 rescued the skeletal phenotype of this mutant mouse, creating an ideal in vivo model to study non-renal 1,25(OH)2D3 production in health and disease. Finally, we confirmed a conserved chromatin landscape in human kidney that is similar to that in mouse. These findings define a finely balanced homeostatic mechanism involving PTH and FGF23 together with protection from 1,25(OH)2D3 toxicity that is responsible for both adaptive vitamin D metabolism and mineral regulation.
2019-05-03 | GSE129585 | GEO
Project description:Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relationships between maternal 25(OH)D concentrations and fetal physiology. Here, we demonstrate active placental uptake of 25(OH)D3 by endocytosis and placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the fetal and maternal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than solely the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer, including transcriptional activation and inflammatory responses. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta; with widespread effects on the placenta itself. These data show complex and synergistic interplay between vitamin D and the placenta, and inform possible interventions to optimise placental function to better support fetal growth and the maternal adaptations to pregnancy.
2021-02-25 | GSE167429 | GEO
Project description:Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relationships between maternal 25(OH)D concentrations and fetal physiology. Here, we demonstrate active placental uptake of 25(OH)D3 by endocytosis and placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the fetal and maternal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than solely the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer, including transcriptional activation and inflammatory responses. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta; with widespread effects on the placenta itself. These data show complex and synergistic interplay between vitamin D and the placenta, and inform possible interventions to optimise placental function to better support fetal growth and the maternal adaptations to pregnancy.
2021-02-25 | GSE167412 | GEO
Project description:Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relationships between maternal 25(OH)D concentrations and fetal physiology. Here, we demonstrate active placental uptake of 25(OH)D3 by endocytosis and placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the fetal and maternal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than solely the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer, including transcriptional activation and inflammatory responses. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta; with widespread effects on the placenta itself. These data show complex and synergistic interplay between vitamin D and the placenta, and inform possible interventions to optimise placental function to better support fetal growth and the maternal adaptations to pregnancy.
2021-02-25 | GSE167411 | GEO
Project description:1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) plays an integral role in calcium homeostasis in higher organisms through its actions in the intestine, kidney and skeleton. Interestingly, while several intestinal genes are known to play a contributory role in calcium homeostasis, the entire caste of key components remains to be identified. To examine this issue, Cyp27b1 null mice on either a normal or a high calcium/phosphate-containing rescue diet were treated with either vehicle or 1,25(OH)2D3 and evaluated 6h later. RNA samples from duodena were then subjected to RNA-seq analysis and the data analyzed bioinformatically. 1,25(OH)2D3 altered expression of large collections of genes raised under either dietary condition. 45 genes were found common to both 1,25(OH)2D3-treated groups, and were comprised of genes previously linked to intestinal calcium uptake including S100g, Trpv6, Atp2b1 and Cldn2 as well as others. An additional distinct network of 56 genes was regulated exclusively by diet. This study revealed a global network of genes in the intestine that both represent direct targets of vitamin D action in mice and are involved in calcium absorption. Male Cyp27b1-/- mice weaned at 3 wk of age were divided into 2 groups of 12 mice each. One group was fed a highly purified vitamin D-deficient diet containing 0.47% Ca, 0.3% P and vitamins A, E, and K (normal diet) while the other was fed the same diet containing 20% lactose, 2% Ca, 1.25% P (rescue diet). At 8 weeks of age, 8 mice per group were administered 1,25(OH)2D3 (2 ng/g body weight (bw)) or vehicle by intraperitoneal injection. Mice were euthanized at 6 h and duodena were collected for RNA-seq analysis. Six samples per experimental group were prepared.
2015-06-03 | E-GEOD-69170 | biostudies-arrayexpress
Project description:Background: Prostate cancer is the second leading cause of cancer mortality among US men. Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1α,25 dihydroxyvitamin D3 (1,25(OH)2D) has anti-cancer effects in cultured prostate cells. Still, the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown. Results: We examined the effect of 1,25(OH)2D (+/- 100 nM, 6, 24, 48 h) on the transcript profile of proliferating RWPE1 cells, an immortalized, non-tumorigenic prostate epithelial cell line that is growth arrested by 1,25(OH)2D (Affymetrix U133 Plus 2.0, n=4/treatment per time and dose). Our analysis revealed many transcript level changes at a 5% false detection rate: 6 h, 1571 (61% up), 24 h, 1816 (60 % up), 48 h, 3566 (38 % up). 288 transcripts were regulated similarly at all time points (182 up, 80 down) and many of the promoters for these transcripts contained putative vitamin D response elements. Functional analysis by pathway or Gene Set Analysis revealed early suppression of WNT, Notch, NF-kB, and IGF1 signaling. Transcripts related to inflammation were suppressed at 6 h (e.g. IL-1 pathway) and suppression of proinflammatory pathways continued at later time points (e.g. IL-17 and IL-6 pathways). There was also evidence for induction of anti-angiogenic pathways and induction of transcripts for protection from oxidative stress or maintenance of cell redox homeostasis at 6 h. Conclusions: Our data reveal of large number of potential new, direct vitamin D target genes relevant to prostate cancer prevention. In addition, our data suggests that rather than having a single strong regulatory effect, vitamin D orchestrates a pattern of changes within prostate epithelial cells that limit or slow carcinogenesis. Experiment Overall Design: RWPE1 cells were treated with medium containing 100 nM of 1,25(OH)2D or vehicle (0.1% ethanol) for 6, 24 or 48 hours (n=4 per treatment, 24 total samples). The transcripts levels in each sample were measured by using the Affymetrix HU133 plus 2.0 GeneChip (Affymetrix, Santa Clara, CA).
2010-01-19 | E-GEOD-15947 | biostudies-arrayexpress