VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription

Singh, Prashant; Long, Mark D.; Battaglia, Sebastiano; Hu, Qiang; Liu, Song; Sucheston‐Campbell, Lara E.; Campbell, Moray J.

doi:10.4161/15592294.2014.989088

Cited by 16 publications

(11 citation statements)

References 76 publications

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“…For example, miR-106b was amongst the most upregulated miRNA in our analysis and targets several down regulated NRs, including PPARA , suggesting that regulation by miRNAs add yet another layer of complexity within the NR network. Together, these observations of reciprocal NR and miRNA co-expression suggest that epigenetic distortion is important to distort the NR superfamily in the prostate(74, 119–121). …”

Section: Introductionmentioning

confidence: 88%

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Long

Campbell

2015

Nuclear Receptor Research

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Nuclear receptors (NR) act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate). Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV) we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g. NR3C2/MR and NR5A2/LRH-1)) whereas others were uniquely down-regulated in one tumor (e.g. NR1B3/RARG). The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression.

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Section: Introductionmentioning

confidence: 88%

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Long

Campbell

2015

Nuclear Receptor Research

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“…It is also noteworthy that datasets have been developed that are aimed at noncoding RNA species. 117,118 Therefore, the diversity of the VDR regulated transcriptome is likely to increase.…”

Section: Identifying Vitamin D Receptor-mediated Transcriptomesmentioning

confidence: 99%

Vitamin D Receptor Signaling and Cancer

Campbell

Trump

2017

Endocrinology and Metabolism Clinics of North America

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The primary biological action of the secosteroid hormone vitamin D (1,25(OH) 2 D 3 ) is to bind to the vitamin D receptor (NR1I1/VDR) and to regulate serum calcium levels. As a downstream consequence, the actions of the receptor control bone formation and maintenance. The first clinical manifestation of insufficient VDR endocrine signaling, rickets, was discovered by Daniel Whistler in the Netherlands in the 17th century; 300 years later, the VDR gene was cloned by Bert O'Malley and coworkers. 1 Between these dates, research into vitamin D was at the forefront of areas of public health, chemistry and biochemistry including the light catalyzed synthesis of vitamin D 3 by Adolf Windaus. For this work, he received the Nobel Prize in Chemistry (1928). Work in the 1960s and 1970s led to analyses of vitamin D endocrine metabolism and led to remarkable strides describing biochemical synthesis of 1,25(OH) 2 D 3 and the diverse biology in which VDR participates.The precursor of 1,25(OH) 2 D 3 , cholecalciferol or vitamin D 3 , is produced in the skin and converted in the liver to 25-hydroxyvitamin D 3 , (25(OH)D 3 ); circulating levels of 25(OH)D 3 serve as a useful index of vitamin D total body stores. A further hydroxylation occurs in the principally in the kidney at the carbon 1 position by 25-hydroxyvitamin D-1α-hydroxylase (encoded by CYP27B1) to produce the biologically active hormone, 1,25(OH) 2 D 3 . A second mitochondrial cytochrome P450 enzyme, the 24-hydroxylase (encoded by CYP24A1), can use both 25(OH)D and 1,25(OH) 2 D 3 as substrates, and is the first step in the inactivation pathway for these metabolites. Because of the direct role 1,25(OH) 2 D 3 plays in control of serum calcium levels, elevated levels of 1,25(OH) 2 D 3 block its synthesis and induce inactivation and accelerate catabolism 2 via induction of CYP24A1, in a classical negative feedback loop.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The first report that VDR actions could control cancer cell growth were discovered partly through serendipity, and partly through logical extension of other studies. Reports in the 1970s identified purified cell fractions that bound 1,25(OH) 2 D 3 with high affinity, 14 and encouraged investigators to begin to consider what were the molecular actions of the VDR in the classic tissues involved in calcium homeostasis, for example, skin, bone, intestine, and kidney. 15 In 1981, Kay Colston and coworkers 16 were first to demonstrate that 1α,25(OH) 2 D 3 at nanomolar concentrations inhibited human melanoma cell proliferation in vitro. That the workers used a cancer cell model was serendipitous; cancer cell models are more readily available to study in cell culture experiments than nonmalignant counterparts, and in this case 16 the cells chosen were available in an adjacent laboratory. Campbell and Trump In parallel, it was also known that retinoids, which are also small lipophilic molecules that target NRs, could drive cell differentiation, for exa...

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“…The regulation of miRNA expression by 1,25(OH) 2 D 3 is an emerging field of interest and has been shown to be part of the signaling cascades responsible for the effects of 1,25(OH) 2 D 3 on cell proliferation, differentiation, apoptosis, and gene regulation (TABLE 1). Sing et al (414) undertook miRNA microarray profiling in different prostate cell lines ranging from nonmalignant to highly malignant cell types and showed that miRNA expression profiles are highly cell-specific. In addition, they demonstrated in nonmalignant RWPE-1 cells that miRNAs are significantly coregulated with mRNA regulation (414).…”

Section: D) Effects On Inflammation In Cancermentioning

confidence: 99%

“…Sing et al (414) undertook miRNA microarray profiling in different prostate cell lines ranging from nonmalignant to highly malignant cell types and showed that miRNA expression profiles are highly cell-specific. In addition, they demonstrated in nonmalignant RWPE-1 cells that miRNAs are significantly coregulated with mRNA regulation (414). Such integration studies will be important to improve miRNA target predictions and to unravel the complex signaling pathways induced by 1,25(OH) 2 D 3 .…”

Section: D) Effects On Inflammation In Cancermentioning

confidence: 99%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,435

1,234

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, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

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VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription

Cited by 16 publications

References 76 publications

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Vitamin D Receptor Signaling and Cancer

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

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