1,25-Dihydroxyvitamin D3 modulates lipid metabolism in prostate cancer cells through miRNA mediated regulation of PPARA

Wang, Wei-Lin Winnie; Welsh, JoEllen; Tenniswood, Martin

doi:10.1016/j.jsbmb.2012.09.033

Cited by 42 publications

(28 citation statements)

References 37 publications

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“…In contrast to the effect of 1,25(OH) 2 D on lipid accumulation reported in this paper, Wang et al [32] demonstrated that treatment of LNCaP prostate cancer cells with 100nM 1,25(OH) 2 D for six days increased neutral lipid accumulation, as measured by Oil Red O staining. A similar result was reported by Lazzaro et al [33].…”

Section: Discussioncontrasting

confidence: 93%

1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase

Wilmanski

Buhman

Donkin

et al. 2017

The Journal of Nutritional Biochemistry

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Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype observed in aggressive breast cancer cells, making lipid metabolism a promising target for breast cancer prevention. In the present studies we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D) on lipid metabolism in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)2D (10 nM) for five and seven days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), respectively. In addition, 1,25(OH)2D treatment for five days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48%±5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)2D mediated regulation and hypothesized that 1,25(OH)2D regulates breast cancer cell lipid metabolism through inhibition of PC. PC mRNA expression was downregulated with 1,25(OH)2D treatment at two (73%±6 relative to vehicle) and five (56%±8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at five days of treatment (54%±12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)2D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)2D regulates lipid metabolism in malignant breast epithelial cells.

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Section: Discussioncontrasting

confidence: 93%

1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase

Wilmanski

Buhman

Donkin

et al. 2017

The Journal of Nutritional Biochemistry

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“…Beyond these candidate studies, a number of investigators have undertaken miRNA microarray analyses (Table 2) and these approaches have identified various networks, including the control of lipid metabolism and PPAR © function (Wang et al, 2013b). It is likely that with the increased application of array approaches and next gen sequencing approaches will identify the key networks downstream of the VDR miRnome.…”

Section: The Vdr Acts In Multimeric Protein Complexes To Regulate Tramentioning

confidence: 99%

Vitamin D and the RNA transcriptome: more than mRNA regulation

Campbell

2014

Front. Physiol.

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The GRCh37.p13 primary assembly of the human genome contains 20805 protein coding mRNA, and 37147 non-protein coding genes and pseudogenes that as a result of RNA processing and editing generate 196501 gene transcripts. Given the size and diversity of the human transcriptome, it is timely to revisit what is known of VDR function in the regulation and targeting of transcription. Early transcriptomic studies using microarray approaches focused on the protein coding mRNA that were regulated by the VDR, usually following treatment with ligand. These studies quickly established the approximate size, and surprising diversity of the VDR transcriptome, revealing it to be highly heterogenous and cell type and time dependent. With the discovery of microRNA, investigators also considered VDR regulation of these non-protein coding RNA. Again, cell and time dependency has emerged. Attempts to integrate mRNA and miRNA regulation patterns are beginning to reveal patterns of co-regulation and interaction that allow for greater control of mRNA expression, and the capacity to govern more complex cellular events. As the awareness of the diversity of non-coding RNA increases, it is increasingly likely it will be revealed that VDR actions are mediated through these molecules also. Key knowledge gaps remain over the VDR transcriptome. The causes for the cell and type dependent transcriptional heterogenetiy remain enigmatic. ChIP-Seq approaches have confirmed that VDR binding choices differ very significantly by cell type, but as yet the underlying causes distilling VDR binding choices are unclear. Similarly, it is clear that many of the VDR binding sites are non-canonical in nature but again the mechanisms underlying these interactions are unclear. Finally, although alternative splicing is clearly a very significant process in cellular transcriptional control, the lack of RNA-Seq data centered on VDR function are currently limiting the global assessment of the VDR transcriptome. VDR focused research that complements publically available data (e.g., ENCODE Birney et al., 2007; Birney, 2012), TCGA (Strausberg et al., 2002), GTEx (Consortium, 2013) will enable these questions to be addressed through large-scale data integration efforts.

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“…This lipogenic effect of 1,25(OH) 2 D 3 is recapitulated in LNCaP cells and is enhanced in the presence of androgen (Esquenet et al, 1997; Wang et al, 2013), highlighting the coordinated effect of AR and VDR signaling. Increase in PPARα expression and its associated lipogenic gene signature, including the elevation of fatty acid synthase ( FASN ) expression, accounts for vitamin D- and androgen-induced lipid production.…”

Section: Intermediate Metabolism: the Warburg Effectmentioning

confidence: 97%

“…In contrast, the miR-17/92 cluster is known to play an oncogenic role and its expression has been linked to more advanced prostate cancer (He et al, 2005; Volinia et al, 2006; Sylvestre et al, 2007; Yu et al, 2008; Diosdado et al, 2009; Trompeter et al, 2011; Yang et al, 2013). In addition, this cluster is a well-validated target for c-Myc, which itself is a direct target of VDR (Simpson et al, 1987; O'Donnell et al, 2005), and a recent report has proposed a regulatory role for the miR-17/92 cluster on PPARα levels, linking miR-17/92 to energy metabolism in prostate cancer cells (Wang et al, 2013). This concurrent analysis of VDR- and AR-mediated mRNA and miRNA expression reveals an extensive and complex transcription network that interconnects c-Myc, PPARα and other transcription factor-mediated signaling, which is only active when both androgen and vitamin D are present.…”

Section: Genomic Overlay Of Vdr and Ar Signalingmentioning

confidence: 99%

Vitamin D, intermediary metabolism and prostate cancer tumor progression

Wang

Tenniswood

2014

Front. Physiol.

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Epidemiological data have demonstrated an inverse association between serum vitamin D3 levels, cancer incidence and related mortality. However, the effects of vitamin D on prostate cancer biology and its utility for prevention of prostate cancer progression are not as well-defined. The data are often conflicting: some reports suggest that vitamin D3 induces apoptosis in androgen dependent prostate cancer cell lines, while others suggest that vitamin D3 only induces cell cycle arrest. Recent molecular studies have identified an extensive synergistic crosstalk between the vitamin D- and androgen-mediated mRNA and miRNA expression, adding an additional layer of post-transcriptional regulation to the known VDR- and AR-regulated gene activation. The Warburg effect, the inefficient metabolic pathway that converts glucose to lactate for rapid energy generation, is a phenomenon common to many different types of cancer. This process supports cell proliferation and promotes cancer progression via alteration of glucose, glutamine and lipid metabolism. Prostate cancer is a notable exception to this general process since the metabolic switch that occurs early during malignancy is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the unique biology of normal prostate cells that harbor a truncated TCA cycle that is required to produce and secret citrate. In prostate cancer cells, the TCA cycle activity is restored and citrate oxidation is used to produce energy for cancer cell proliferation. 1,25(OH)2D3 and androgen together modulates the TCA cycle via transcriptional regulation of zinc transporters, suggesting that 1,25(OH)2D3 and androgen maintain normal prostate metabolism by blocking citrate oxidation. These data demonstrate the importance of androgens in the anti-proliferative effect of vitamin D in prostate cancer and highlight the importance of understanding the crosstalk between these two signaling pathways.

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1,25-Dihydroxyvitamin D3 modulates lipid metabolism in prostate cancer cells through miRNA mediated regulation of PPARA

Cited by 42 publications

References 37 publications

1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase

1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase

Vitamin D and the RNA transcriptome: more than mRNA regulation

Vitamin D, intermediary metabolism and prostate cancer tumor progression

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