Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35401 | GEO | 2012/12/19
SECONDARY ACCESSION(S): PRJNA152789
REPOSITORIES: GEO
Similar Datasets
Project description:We conducted gene expression profilling of common prostate cell lines for comparison with genome-wide DNA methylation profiles for the same cell lines to study the impact of differential DNA methylation in prostate cancer. Total RNA was extracted from 3 biological replicate sets of PrEC, RWPE-1, DU 145, and LNCaP cells. This Series represents the gene expression profiling data only. The methyl-Seq data were submitted directly to SRA and are represented by accession SRA049689.1.
2012-12-19 | E-GEOD-35401 | biostudies-arrayexpress
Project description:Recent epidemiologic data show that low serum cholesterol level as well as statin use is associated with a decreased risk of developing aggressive or advanced prostate cancer, suggesting a role for cholesterol in aggressive prostate cancer development. Intracellular cholesterol promotes prostate cancer progression as a substrate for de novo androgen synthesis and through regulation of AKT signaling. By conducting next-generation sequencing-based DNA methylome analysis, we have discovered marked hypermethylation at the promoter of the major cellular cholesterol efflux transporter, ABCA1, in LNCaP prostate cancer cells. ABCA1 promoter hypermethylation renders the promoter unresponsive to transactivation and leads to elevated cholesterol levels in LNCaP. ABCA1 promoter hypermethylation is enriched in intermediate- to high-grade prostate cancers and not detectable in benign prostate. Remarkably, ABCA1 downregulation is evident in all prostate cancers examined, and expression levels are inversely correlated with Gleason grade. Our results suggest that cancer-specific ABCA1 hypermethylation and loss of protein expression direct high intracellular cholesterol levels and hence contribute to an environment conducive to tumor progression.
| S-EPMC3563867 | biostudies-literature
Project description:Plasmalogen biosynthesis is regulated by modulating fatty acyl-CoA reductase 1 stability in a manner dependent on cellular plasmalogen level. However, physiological significance of the regulation of plasmalogen biosynthesis remains unknown. Here we show that elevation of the cellular plasmalogen level reduces cholesterol biosynthesis without affecting the isoprenylation of proteins such as Rab and Pex19p. Analysis of intermediate metabolites in cholesterol biosynthesis suggests that the first oxidative step in cholesterol biosynthesis catalyzed by squalene monooxygenase (SQLE), an important regulator downstream HMG-CoA reductase in cholesterol synthesis, is reduced by degradation of SQLE upon elevation of cellular plasmalogen level. By contrast, the defect of plasmalogen synthesis causes elevation of SQLE expression, resulting in the reduction of 2,3-epoxysqualene required for cholesterol synthesis, hence implying a novel physiological consequence of the regulation of plasmalogen biosynthesis.
| S-EPMC4661398 | biostudies-literature
Project description:Aberrant regulation of cholesterol homeostasis is associated with obesity as well as multiple types of cancer. However, the mechanism behind these is largely missing. Here, we show that microRNA (miRNA)-128-2 is not only a pro-apoptotic microRNA but it also alters the expression of genes involved in cellular cholesterol homeostasis. Cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1) is a mechanism for cells to eliminate excess cholesterol and prevent cellular cholesterol accumulation. The regulation of these pathways is complex with transcriptional regulation by sterol-regulatory element-binding protein (SREBP) and liver X receptor/retinoid X receptor (RXR) transcription factors but poorly understood at the post-transcriptional levels. MiR-128-2 increases the expression of SREBP2 and decreases the expression of SREBP1 in HepG2, MCF7 and HEK293T cells independent of sirtuin 1 (SIRT1) status. MiR-128-2 inhibits the expression of ABCA1, ABCG1 and RXR? directly through a miR-128-2-binding site within their respective 3'untranslated regions. The administration of miR-128-2 leads to decline in the protein and mRNA levels of ABCA1, ABCG1 and RXR?. Conversely, anti-miRNA treatment leads to increased ABCA1, ABCG1 and RXR? expression. The inverse correlation between miR-128-2 and its targets viz. ABCA1 and ABCG1 was also established during high-fat diet in different mice tissues. Our data show that cholesterol efflux is attenuated by miR-128-2 overexpression and, conversely, stimulated by miR-128-2 silencing. Further, we also observed the induction of ER stress response by miR-128-2. In this study, we provide the first evidence of miR-128-2 to be a new regulator of cholesterol homeostasis. Our study shows dual role of miR-128-2, as a pro-apoptotic molecule as well as a regulator of cholesterol homeostasis.
| S-EPMC3763462 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE32344: Expression profilling of prostate cancer VCaP and VCS2 cells GSE32345: Genome-wide maps of AR binding in prostate cancer cell lines VCaP and VCS2 Refer to individual Series
2012-02-01 | E-GEOD-32356 | biostudies-arrayexpress
Project description:Trivalent chromium (Cr3+) is an essential micronutrient. Findings since the 1950s suggest that Cr3+ might benefit cholesterol homeostasis. Here we present mechanistic evidence in support of this role of Cr3+.High-density lipoprotein cholesterol generation in 3T3-L1 adipocytes, which are rendered ineffective by the hyperinsulinemia that is known to accompany disorders of lipid metabolism, was corrected by Cr3+. Mechanistically, Cr3+ reversed hyperinsulinemia-induced cellular cholesterol accrual and associated defects in cholesterol transporter ATP-binding cassette transporter-A1 trafficking and apolipoprotein A1-mediated cholesterol efflux. Moreover, direct activation of AMP-activated protein kinase, which is known to be activated by Cr3+, or inhibition of hexosamine biosynthesis pathway activity, which is known to be elevated by hyperinsulinemia, mimics Cr3+ action.These findings suggest a mechanism of Cr3+ action that fits with long-standing claims of its role in cholesterol homeostasis. Furthermore, these data imply a mechanistic basis for the coexistence of dyslipidemia with hyperinsulinemia.
| S-EPMC3081388 | biostudies-other
Project description:In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662-73. ©2017 AACR.
| S-EPMC5687884 | biostudies-literature
Project description:Mammalian spermatozoa undergo important plasma membrane maturation steps during epididymal transit. Among these, changes in lipids and cholesterol are of particular interest as they are necessary for fertilization. However, molecular mechanisms regulating these transformations inside the epididymis are still poorly understood. Liver X receptors (LXRs), the nuclear receptors for oxysterols, are of major importance in intracellular cholesterol homeostasis, and LXR(-/-)-deficient male mice have already been shown to have reduced fertility at an age of 5 months and complete sterility for 9-month-old animals. This sterility phenotype is associated with testes and caput epididymides epithelial defects. The research presented here was aimed at investigating how LXRs act in the male caput epididymidis by analyzing key actors in cholesterol homeostasis. We show that accumulation of cholesteryl esters in LXR(-/-) male mice is associated with a specific loss of ABCA1 and an increase in apoptosis of apical cells of the proximal caput epididymidis. ATP-binding cassette G1 (ABCG1) and scavenger receptor B1 (SR-B1), two other cholesterol transporters, show little if any modifications. Our study also revealed that SR-B1 appears to have a peculiar expression pattern along the epididymal duct. These results should help in understanding the functional roles of LXR in cholesterol trafficking processes in caput epididymidis.
| S-EPMC2724773 | biostudies-literature
Project description:Mutations in SPG11, leading to loss of spatacsin function, impair the formation of membrane tubules in lysosomes and cause lysosomal lipid accumulation. However, the full nature of lipids accumulating in lysosomes and the physiological consequences of such accumulation are unknown. Here we show that loss of spatacsin inhibits the formation of tubules on lysosomes and prevents the clearance of cholesterol from this subcellular compartment. Accumulation of cholesterol in lysosomes decreases cholesterol levels in the plasma membrane, enhancing the entry of extracellular calcium by store-operated calcium entry and increasing resting cytosolic calcium levels. Higher cytosolic calcium levels promote the nuclear translocation of the master regulator of lysosomes TFEB, preventing the formation of tubules and the clearance of cholesterol from lysosomes. Our work reveals a homeostatic balance between cholesterol trafficking and cytosolic calcium levels and shows that loss of spatacsin impairs this homeostatic equilibrium.
| S-EPMC6797781 | biostudies-literature
Project description:The expression of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) in the brain and its role in the lipidation of apolipoproteins indicate that ABCA1 may play a critical role in brain cholesterol metabolism. To investigate the role of ABCA1 in brain cholesterol homeostasis and trafficking, we characterized mice that specifically lacked ABCA1 in the CNS, generated using the Cre/loxP recombination system. These mice showed reduced plasma high-density lipoprotein (HDL) cholesterol levels associated with decreased brain cholesterol content and enhanced brain uptake of esterified cholesterol from plasma HDL. Increased levels of HDL receptor SR-BI in brain capillaries and apolipoprotein A-I in brain and CSF of mutant mice were evident. Cholesterol homeostasis changes were mirrored by disturbances in motor activity and sensorimotor function. Changes in synaptic ultrastructure including reduced synapse and synaptic vesicle numbers were observed. These data show that ABCA1 is a key regulator of brain cholesterol metabolism and that disturbances in cholesterol transport in the CNS are associated with structural and functional deficits in neurons. Moreover, our findings also demonstrate that specific changes in brain cholesterol metabolism can lead to alterations in cholesterol uptake from plasma to brain.
| S-EPMC2678874 | biostudies-literature