Cited by Impact of Oxysterols on Cell Death, Proliferation, and Differentiation Induction: Current Status

Dietary Lipids Modulate Notch Signaling and Influence Adult Intestinal Development and Metabolism in Drosophila DOI

Rebecca Obniski, Matthew Sieber, Allan C. Spradling

et al.

Developmental Cell, Journal Year: 2018, Volume and Issue: 47(1), P. 98 - 111.e5

Published: Sept. 13, 2018

Language: Английский

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Oxysterols and nuclear receptors DOI

Liqian Ma, Erik R. Nelson

Molecular and Cellular Endocrinology, Journal Year: 2019, Volume and Issue: 484, P. 42 - 51

Published: Jan. 18, 2019

Language: Английский

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Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma DOI

Mingzhi Han, Shuai Wang, Ning Yang

et al.

EMBO Molecular Medicine, Journal Year: 2019, Volume and Issue: 12(1)

Published: Nov. 28, 2019

Article28 November 2019Open Access Transparent process Therapeutic implications of altered cholesterol homeostasis mediated by loss CYP46A1 in human glioblastoma Mingzhi Han Shandong Key Laboratory Brain Function Remodeling, Department Neurosurgery, Qilu Hospital University and Institute Brain-Inspired Science, University, Jinan, China Biomedicine, Bergen, Norway Search for more papers this author Shuai Wang orcid.org/0000-0002-0454-5281 Ning Yang Xu Wenbo Zhao Halala Sdik Saed Thomas Daubon INSERM U1029, Institut Nationale de la Santé et Recherche Médicale, Pessac, France Bordeaux, Bin Huang Anjing Chen School Medicine, Gang Li Hrvoje Miletic Pathology, Haukeland Hospital, Frits Thorsen orcid.org/0000-0002-7762-3703 The Molecular Imaging Center, Rolf Bjerkvig Corresponding Author [email protected] orcid.org/0000-0002-9622-7263 NorLux Neuro-Oncology Laboratory, Oncology, Luxembourg Health, City, Xingang orcid.org/0000-0002-0878-0211 Jian orcid.org/0000-0002-9482-5227 Information Han1,2,‡, Wang1,‡, Yang1, Wang1, Zhao1, Saed2, Daubon3,4, Huang1, Chen1,5, Li1, Miletic2,6, Thorsen2,7, *,2,8,‡, *,1,‡ *,1,2,‡ 1Shandong 2Department 3INSERM 4University 5School 6Department 7Department 8NorLux ‡These authors contributed equally to work as senior *Corresponding author. Tel: +47 55586042; E-mail: +86 0537 82169428; 82169429; EMBO Mol Med (2020)12:e10924https://doi.org/10.15252/emmm.201910924 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Dysregulated metabolism is hallmark many cancers, (GBM), but its role disease progression not well understood. Here, we identified 24-hydroxylase (CYP46A1), brain-specific enzyme responsible elimination through conversion into 24(S)-hydroxycholesterol (24OHC), one most dramatically dysregulated genes GBM. was significantly decreased GBM samples compared with normal brain tissue. A reduction expression associated increasing tumour grade poor prognosis gliomas. Ectopic suppressed cell proliferation vivo growth 24OHC levels. RNA-seq revealed that treatment cells regulation LXR SREBP signalling. Efavirenz, an activator known penetrate blood–brain barrier, inhibited vivo. Our findings demonstrate critical regulator cellular CYP46A1/24OHC axis potential therapeutic target. Synopsis Loss partially caused excessive accumulation contributing maintenance viability malignant state. anti-HIV drug, crosses BBB shows anti-tumor effect though activation axis. promotes behavior inhibits via catalyzing production 24(S)-hydroxycholesterol. has favorable penetration. Drug repurposing Efavirenz CYP46A1-24OHC Introduction Glioblastoma (GBM) common primary adults (Fack al, 2017; Lhomond 2018). Despite aggressive therapy, maximal surgical resection followed radiotherapy temozolomide treatment, median patient survival 14.6 months from initial diagnosis (Stupp 2005). New strategies are therefore urgently needed. Emerging evidence linked disrupted cancer development (Bovenga 2015; Kuzu 2016; Cheng However, epidemiological data remain contradictory regarding relationship between risk serum levels, suggesting circulating levels alone have marginal effects on (Silvente-Poirot Oxysterols oxygenated derivatives participate metabolism. They derived diet or generated endogenous tissues. include 24-hydroxycholesterol 25-hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC) ring oxysterols (Janowski 1996; Berrodin 2010) to, addition regulation, modulate signalling pathways such Hedgehog, Wnt MAPK (Kloudova 2017). In neurodegenerative cancer, interact specific proteins transcription factors, liver X receptors (LXR) oxysterol-binding protein insulin-induced gene 1 (INSIG1) Recently, it been shown 27OHC can inhibit prostate depletion intracellular (Alfaqih Yet, others shown, breast cells, induces epithelial-to-mesenchymal transition (EMT) leading increased (Torres 2011; Wu 2013). It also subtype early-stage hepatocellular carcinoma (Jiang 2019). GBM, notion fuel supported following evidence. First, novo synthesis astrocytes exogenous uptake up-regulation low-density lipoprotein receptor (LDLR) (Villa 2016). Second, leads efflux At present, mechanisms causing dysregulation clear, especially regard oxysterol loss. mammals, tightly regulated complex network centred around two groups sterol-regulatory binding (SREBPs) (LXRs), involved import, export, synthesis, esterification (Ikonen, 2008). SREBPs mainly promote genes, HMGCR LDLR, when decrease. LXRs respond inducing ABCA1 ABCG1, LDLR degradation induction E3 ubiquitin ligase IDOL (Zelcer 2009). Targeting these be effective strategy inhibiting animal models (An Weiss, Cancer clearly developed order support their growth. Cholesterol might represent key factors GBMs unclear. used large-scale silico analyses whole-transcriptome databases identify homeostasis. One down-regulated (24OHC) (Moutinho emerged prognostic marker patients, functional studies, overexpression pharmacological vitro results show changes targeting may provide new opportunity therapy. Results level determined difference brain. Gene set enrichment analysis (GSEA) based Rembrandt (n = 217) tissues 28) displayed distinct metabolic processes (Appendix Fig S1A). however, positively (adjusted P < 0.05, respectively; Appendix S1A), which consistent previous reports indicating depend synthesized To confirm cholesterol, lines (LN229 U251) GSCs (GBM#P3) were cultured media FBS lipoprotein-deficient (LPDS). Growth curves slower LPDS after 5 days (P 0.01). μg/ml LDL (the highest content) medium rescued S1B–D). These importance reported previously (Guo Geng suppressor candidate cholesterol-related performed bioinformatic publicly available genomic datasets. signature 176 biology Ontologies Through differential using dataset, uncovered total 13 differentially expressed tissue (Fig 1A B). regulator, CYP46A1, (log2 fold change 2.335, adjusted 5.85E-25). Differential Chinese Glioma Genome Atlas (CGGA) dataset transcripts 1.966, 4.63E-09) 128) 5; EV1A–C). Univariate Cox regression patients screen values. After ranking P-value, among top 3 (APOBR, CELA3A CYP46A1) EV1D). By analysing (TCGA) pan-cancer 31 different types, found LGG S2A). further confirmed several public glioma datasets (over 1,500 enrolled; 0.01, S2B). Figure 1. Expression homeostasis, lost A. Heatmap glioblastomas dataset. values z-transformed coloured red high blue low expression, indicated scale bar. B. Volcano plot showing (log2) versus Data obtained C. Representative images IHC staining pathological grades gliomas 64). Scale bar 30 μm. D. Quantification 6) 58). E. adjacent case. F. tumours TCGA 2016 WHO classification. mean ± standard error (SEM; n 667). ***P 0.0001. Statistical significance one-way ANOVA. G. molecular subtypes Shown means SEM 245). H–I. Kaplan–Meier OS PFS CGGA P-values log-rank test. Download figure PowerPoint Click here expand figure. EV1. correlates strongly features 5) samples. Venn both 20 overall intra-tumoral pattern IVY (http://glioblastoma.alleninstitute.org/). highly at edge (which comprised cells) other regions S2C). Single-cell (Darmanis 2017) demonstrated neurons, oligodendrocyte precursor (OPCs) lesser extent S2D). examined S2E). Normal (NHAs) abundant while (GBM#P3, GBM#05, GBM#BG7, LN229, U251 LN18) showed much lower expression. reduced level, independent cohort 58) 6). cytoplasmic. consistently (5/6; 88.3%) (14/24; 58.3%) (6/34; 17.6%), 1C D). sample absent 1E). Human Protein 17) corroborated results, confirming EV2A), EV2B C). EV2. Decreased high-grade comparison A–C. quantification provided cerebellum, cerebral cortex hippocampus, 4 low-grade 8 glioma). 200 scores stained estimated each type, (not detected high), intensity (negative strong), quantity > 75%) sub-cellular locations positive staining. We subsequently assessed classification gliomas, data. higher three (LGG-Oligo, LGG-Astro LGG-IDHwt) GBM-IDHmt GBM-IDHwt 1F). Although there general down-regulation brain, observed Neural 1G), favourable prognosis, relative Verhaak-2010 (Noushmehr 2010). address why GBMs, promoter/enhancer combined chromatin immunoprecipitation sequencing (ChIP-seq) GEO ENCODE databases. H3K27ac peaks (marker active promoters) within promoter region S3A). enhancer landscape across matched pairs differentiated (DGCs). enhancers mRNA tended decrease GSC DGC, measured ChIP-seq (H3K27ac H3K4me3 peak levels) S3A–C). validated ChIP-qPCR Western blot S3D E). Taken together, abnormal histone modifications explain correlate worse determine clinical (based value) exhibited better (OS) progression-free (PFS) 1H I). indicator value TCGA, Phillips S4A–C). univariate multivariate (HR 0.390, 95% CI 0.262 0.581, 0.001; Table S1) trend patients. Collectively, emphasize relevance attenuates Next, vitro. Lentivirus over-express LN18 GBM#P3, qRT–PCR 2A) 2B S5A). Cell lenti-CYP46A1 lenti-Ctrl 0.01; 2C). attenuated colony formation 0.05; 2D). Furthermore, tumorsphere formation, stem-like property S5B 2. Restoration intracranial xenografts LN229 GBM#P3 transfected lentivirus expressing (lenti-CYP46A1) control sequence (lenti-Ctrl). GAPDH internal control. 3). LN229: 0.0001; GBM#P3: two-sided Student's t-test. cells. infected trypan **P 0.003; 0.002. Colony-forming assay lenti-CYP46A1. *P 0.013; LN18: 0.012. H&E orthotopic 2 mm. curve tumour-bearing mice injected per group). test assess statistical significance. PCNA cleaved caspase-3 tumours. 100 GBM#P3-lenti-CYP46A1 GBM#P3-lenti-control intracranially evaluate For growth, haematoxylin eosin (HE) 2E), prolonged 2F). Overexpression led apoptotic 2G, S5D tumour-suppressive encodes cytochrome P450 oxidase, sterol 24-hydroxylase, function convert 3A). characterized 3) S6A).

Language: Английский

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LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies DOI

Giovanna Revilla, Lídia Cedó, Mireia Tondo

et al.

Seminars in Cancer Biology, Journal Year: 2020, Volume and Issue: 73, P. 134 - 157

Published: Nov. 26, 2020

Language: Английский

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Impact of Oxysterols on Cell Death, Proliferation, and Differentiation Induction: Current Status DOI

Fábio Alessandro de Freitas, Débora Levy, Amira Zarrouk

et al.

Cells, Journal Year: 2021, Volume and Issue: 10(9), P. 2301 - 2301

Published: Sept. 3, 2021

Oxysterols are oxidized derivatives of cholesterol produced by enzymatic activity or non-enzymatic pathways (auto-oxidation). The oxidation processes lead to the synthesis about 60 different oxysterols. Several oxysterols have physiological, pathophysiological, and pharmacological activities. effects on cell death processes, especially apoptosis, autophagy, necrosis, oxiapoptophagy, as well their action proliferation, reviewed here. These effects, also observed in several cancer lines, could potentially be useful treatment. differentiation described. Among them, properties stimulating osteogenic mesenchymal stem cells while inhibiting adipogenic may regenerative medicine.

Language: Английский

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