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Abstracts of the 4Th International Symposium on Vitamin D and Analogs in Cancer Prevention and Therapy

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Abstracts of the 4Th International Symposium on Vitamin D and Analogs in Cancer Prevention and Therapy ANTICANCER RESEARCH 31: 1489-1512 (2011) ABSTRACTS OF THE 4TH INTERNATIONAL SYMPOSIUM ON VITAMIN D AND ANALOGS IN CANCER PREVENTION AND THERAPY 20-21 May, 2011 Schlossberg Hotel, Homburg/Saar, Germany Local Organizing Committee J. Reichrath1, M. Friedrich2, T. Vogt1 1Department of Dermatology, Venereology and Allergology, The Saarland University Hospital, Homburg/Saar, Germany; 2Klinik fü r Frauenheilkunde und Geburtshilfe, HELIOS Klinikum, Krefeld, Germany Scientific Board C. Carlberg, Kuopio, Finland M.F. Holick, Boston, MA, U.S.A. D. Feldman, Stanford, CA, U.S.A. J. Reichrath, Homburg/Saar, Germany M. Friedrich, Krefeld, Germany T. Vogt, Homburg/Saar, Germany Under the Auspices of Ministerium für Gesundheit und Verbraucherschutz des Saarlandes Deutsche Forschungsgemeinschaft (DFG) Deutsche Gesellschaft für Ernährung e.V. (DGE) Saarländisches Tumorzentrum Official Sponsors (until 15.03.2011) Almirall Hermal GmbH, Germany Cerbios-Pharma SA, Switzerland Chromsystems Instruments and Chemicals, Germany Diasorin GmbH, Germany IDS Immunodiagnostic Systems GmbH, Germany Immundiagnostik AG, Germany Janssen-Cilag GmbH, Germany JW Holding GmbH, Germany Merck Serono GmbH, Germany Oy Verman AG, Finland Photomedverband e.V., Germany Procter & Gamble GmbH, Germany UV-Foundation, U.S.A. 1489 ANTICANCER RESEARCH 31: 1489-1512 (2011) 1 mouse and human genomes in osteoblast and intestinal/colon D-LIGHTFUL VITAMIN D FOR HEALTH cells upon activation by 1,25(OH)2D3. RXR co-binds to the majority of these sites as well, as do numerous coregulatory M.F. Holick factors. Surprisingly, most of these sites are located distal to Boston University School of Medicine, Boston, MA, U.S.A. regulated gene promoters. In bone cells, many of these sites overlap with those of the master regulator RUNX2 and the Vitamin D is the sunshine vitamin. During exposure to sunlight, chromatin remodeler C/EBPβ, whereas in intestinal cells, these 7-dehydrocholesterol absorbs ultraviolet B radiation resulting in sites frequently contain both C/EBPβ and the homeobox factor the cutaneous production of previtamin D3. Once formed, Cdx2. These regulatory regions modulate the expression of genes previtamin D3 undergoes an internal isomerization resulting in for CYP24A1, VDR, SPP1, RANKL, CBS and others in the production of vitamin D3. During prolonged exposure to osteoblasts, and CYP24A1, CYP3A4, CYP2B6, ABCB1, and sunlight, pre-vitamin D3 and vitamin D3 absorb UVB radiation PADI1 in intestinal cells. Interestingly, ChIP-seq analysis of resulting in their conversion to a variety of biologically inert (on TCF4/β-catenin binding revealed numerous sites of action on calcium metabolism) products. A variety of factors markedly target genes for the Wnt activation pathway in colorectal cancer influence the production of vitamin D in the skin including skin cells. A small but signficant colocalization of both VDR/RXR pigmentation, sunscreen use, time of day, season of the year, and TFC4/β-catenin sites highlighted a number of growth latitude and aging. Once formed, vitamin D undergoes regulating genes that included c-FOS and c-MYC. The funtional sequential hydroxylations in the liver and kidneys to form 25- activity of 1,25(OH)2D3 on these latter genes has been explored. hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D These new approaches to the study of gene expression have [1,25(OH)2D], respectively. 1,25(OH)2D plays an important role revealed an important set of overarching principles of in maintaining calcium homeostasis and maximizing bone 1,25(OH)2D3 action in cells. health. There is mounting evidence that increasing blood levels of 25(OH)D reduces risk of many chronic illnesses including autoimmune diseases, cancer, heart disease and type II diabetes. 3 There is also evidence for its reducing the risk of infectious A GENOME-WIDE PERSPECTIVE diseases, preeclampsia and requiring a primary Cesarean ON VITAMIN D SIGNALING section. Improving vitamin D status has also been associated Carsten Carlberg with improvement in neurocognitive function and in muscle strength. Serum 25(OH)D>30 ng/m can be achieved in most University of Eastern Finland, Kuopio, Finland children by ingesting 1,000 IU of vitamin D a day and for teenagers and adults 2,000 IU of vitamin D a day. As a model system for a genome- and transcriptome-wide understanding of the primary actions of the nuclear hormone 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) and its receptor 2 VDR, we selected THP-1 human monocytic leukemia cells. NEW PARADIGMS FOR GENE REGULATION Mircoarray time course experiments over a period of 4 hours BY 1,25-DIHYDROXYVITAMIN D 3 after 1α,25(OH)2D3 treatment demonstrated that the mRNA expression of close to 2,000 of the 17,000 expressed genes in J.W. Pike, M.B. Meyer, P.D. Goetsch, S.-M. Lee THP-1 cells is statistical significantly affected, although many Department of Biochemistry, University of Wisconsin, of these effects are only transient and of lower magnitude. Madison, WI, U.S.A. ChIP-Seq analysis at time point 40 min after 1α,25(OH)2D3 treatment identified 2340 genomic VDR binding locations, 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) exerts biological 520 of which occur already in absence of ligand, but most of activity in target tissues by regulating the expression of genes them do not contain a DR3-type response element (RE), while involved in cellular differentiation and function. These activities many of the 1171 sites that light up specifically after VDR are mediated by VDR which binds to DNA sequences at target activation carry at least one DR3-type RE. Interestingly, most genes and functions to nucleate coregulatory complexes essential of the up-regulated 1α,25(OH)2D3 target genes show VDR for gene modulation. To examine these concepts, we have used binding within 400 kb of their transcription start site (TSS), both gene expression studies and chromatin immunoprecipitation while this applied only for some less than half of the down- (ChIP) linked to deep sequencing techniques (ChIP-seq) to regulated genes. The genomic VDR loci showed quite a explore sites of action of VDR and its partner RXR in bone and variation in their gene regulatory scenarios ranging from a intestinal cells. We have also used these techniques to examine single VDR location close to the target gene TSS, more colocalization with other DNA binding proteins, lineage-specific complex ones with one VDR location more distal to the TSSs factors and coregulators. VDR binds to several thousand sites on of two target genes and very complex ones with many VDR 0250-7005/2011 $2.00+.40 1491 ANTICANCER RESEARCH 31: 1489-1512 (2011) locations in a cluster of target genes. In conclusion, VDR has The nuclear vitamin D receptor (VDR) binds 1,25- far more than expected target genes in THP-1 cells and ligand dihydroxyvitamin D3 (1,25D), its high affinity endocrine binding shifts genome-wide VDR locations to distal regions ligand, to signal intestinal calcium and phosphate absorption of its primary target genes carrying DR3-type REs that occur plus bone remodeling to prevent osteoporotic fractures. in a large variation of regulatory constellations. 1,25D/VDR also controls gene expression to delay aging and chronic diseases such as cancer, arteriosclerosis, stroke, and infection. 1,25D/VDR regulates the transcription of genes 4 relevant to cancer, e.g., CYP27B1, CYP24A1, and FGF23. SOLUTION STRUCTURES OF NUCLEAR Circulating 25-hydroxyvitamin D3 is converted to 1,25D RECEPTOR HETERODIMERS locally by extrarenal CYP27B1, and binds VDR to promote anticancer actions. Moreover, vitamin D affects the expression Natacha Rochel1, Fabrice Ciesielski1, Igor Orlov1, of a host of oncogenes, their receptors, tumor suppressors, and Julien Godet2, Manfred Roessle3, Carole Peluso-Iltis1, Yves DNA repair systems. VDR also affects Wnt signaling through Mély2, Bruno Klaholz1, Dmitri I. Svergun3, Dino Moras1 direct interaction with β-catenin, and blunts β-catenin 1Département de Biologie et de Génomique Structurales, mediated transcription in colon cancer cells to attenuate their IGBMC (Institut de Génétique et de Biologie Moléculaire et growth. Additionally, novel VDR ligands, such as curcumin, Cellulaire) (UMR7104 CNRS, U964 INSERM, UDS), can activate VDR signaling, with a differential gene expression 2Laboratoire de Biophotonique et Pharmacologie, Faculté de profile to synergize with vitamin D in lowering the risk of Pharmacie, UMR 7213 du CNRS, colon tumorigenesis. VDR also binds the carcinogenic Universite’ de Strasbourg, 67401 Illkirch, France; secondary bile acid, lithocholic acid, to induce its CYP3A4- 3European Molecular Biology Laboratory, Hamburg mediated detoxification. In conclusion, we hypothesize that Outstation, 22603 Hamburg, Germany the prevention of colon cancer by VDR activation serves as a paradigm for understanding the mechanisms whereby VDR Nuclear receptors (NRs) control numerous physiological attenuates aging and chronic disease in the cardiovascular, processes through the regulation of gene expression. We have immune, and musculoskeletal systems. determined the solution structures of three functional heterodimers RXR/RAR, RXR/PPAR and RXR/VDR bound to natural hormone response elements in presence or absence 6 of coactivator, using Small Angle X-ray Scattering and VITAMIN D AND COLON CANCER: REGULATION Fluorescence Resonance Energy Transfer techniques. In AND EFFECTS OF SPROUTY-2 AND DICKKOPF-1 contrast to the reported crystal structure of RXR/PPAR, the GENES AND PROTEOMIC ANALYSIS structures in solution exhibit an extended asymmetric
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