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Pathway analysis identifies perturbation of genetic networks induced by butyrate in a bovine kidney epithelial cell line

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Abstract

Ruminant species have evolved to metabolize the short-chain volatile fatty acids (VFA), acetate, propionate, and butyrate, to fulfill up to 70% of their nutrient energy requirements. The inherent VFA dependence of ruminant cells was exploited to add a level of increased sensitivity to the study of the role of butyrate gene-response elements in regulatory biochemical pathways. Global gene expression profiles of the bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. The detailed mechanisms by which butyrate induces cell growth arrest and apoptosis were analyzed using the Ingenuity Pathways Knowledge Base. The functional category and pathway analyses of the microarray data revealed that four canonical pathways (Cell cycles: G2/M DNA damage checkpoint, and pyrimidine metabolism; G1/S checkpoint regulation and purine metabolism) were significantly perturbed. The biologically relevant networks and pathways of these genes were also identified. IGF2, TGFB1, TP53, E2F4, and CDC2 were established as being centered in these genomic networks. The present findings provide a basis for understanding the full range of the biological roles and the molecular mechanisms that butyrate may play in animal cell growth, proliferation, and energy metabolisms.

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References

  • Abdel-Aziz HO, Takasaki I, Tabuchi Y, Nomoto K, Murai Y et al (2006) High-density oligonucleotide microarrays and functional network analysis reveal extended lung carcinogenesis pathway maps and multiple interacting genes in NNK [4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone] induced CD1 mouse lung tumor. J Cancer Res Clin Oncol 2006 Sep 15; [Epub ahead of print] PMID:16977459

  • Adams JM (2003) Ways of dying: multiple pathways to apoptosis. 17:2481–2495

  • Bergman EN (1990) Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 70:567–590

    PubMed  CAS  Google Scholar 

  • Bolstad BM, Irizarry RA, Astrand M, Speed TP (2003) A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19:185–193

    Article  PubMed  CAS  Google Scholar 

  • Bommireddy R, Saxena V, Ormsby I, Yin M, Boivin GP et al (2003) TGF-beta 1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes. J Immunol 170:4612–4622

    PubMed  CAS  Google Scholar 

  • Bugaut M (1987) Occurrence, absorption and metabolism of short chain fatty acids in the digestive tract of mammals. Comp Biochem Physiol B 86:439–472

    Article  PubMed  CAS  Google Scholar 

  • Butt AJ, Williams AC (2001) IGFBP-3 and apoptosis—a license to kill? Apoptosis 6:199–205

    Article  PubMed  CAS  Google Scholar 

  • Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437:1032–1037

    Article  PubMed  CAS  Google Scholar 

  • Chen JS, Faller DV, Spanjaard RA (2003) Short-chain fatty acid inhibitors of histone deacetylases: promising anticancer therapeutics? Current Cancer Drug Targets 3:219–236

    Article  PubMed  CAS  Google Scholar 

  • Chiba T, Yokosuka O, Fukai K, Kojima H, Tada M et al (2004) Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology 66:481–491

    Article  PubMed  CAS  Google Scholar 

  • Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    Article  PubMed  CAS  Google Scholar 

  • Dashwood RH, Myzak MC, Ho E (2006) Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? Carcinogenesis 27:344–349

    Article  PubMed  CAS  Google Scholar 

  • Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868

    Google Scholar 

  • Emenaker NJ, Calaf GM, Cox D, Basson MD, Qureshi N (2001) Short-chain fatty acids inhibit invasive human colon cancer by modulating uPA, TIMP-1, TIMP-2, mutant p53, Bcl-2, Bax, p21 and PCNA protein expression in an in vitro cell culture model. J Nutr 131:3041S–3046S

    PubMed  CAS  Google Scholar 

  • Gassull MA, Cabre E (2001) Nutrition in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care 4:561–569

    Article  PubMed  CAS  Google Scholar 

  • Hague A, Paraskeva C (1995) The short-chain fatty acid butyrate induces apoptosis in colorectal tumour cell lines. Eur J Cancer Prev 4:359–364

    Article  PubMed  CAS  Google Scholar 

  • Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B et al (2003a) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31:e15

    Article  PubMed  Google Scholar 

  • Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ et al (2003b) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264

    Article  PubMed  Google Scholar 

  • Johnson IT (2002) Anticarcinogenic effects of diet-related apoptosis in the colorectal mucosa. Food Chem Toxicol 40:1171–1178

    Article  PubMed  CAS  Google Scholar 

  • Joseph J, Wajapeyee N, Somasundaram K (2005) Role of p53 status in chemosensitivity determination of cancer cells against histone deacetylase inhibitor sodium butyrate. Int J Cancer 115:11–18

    Article  PubMed  CAS  Google Scholar 

  • Jung JW, Cho SD, Ahn NS, Yang SR, Park JS et al (2005) Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate. Cancer Lett 225:199–206

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi I, Jin L, Ruebel KH, Bayliss JM, Hidehiro O et al (2003) Regulation of cell growth and expression of 7B2, PC2, and PC1/3 by TGFbeta 1 and sodium butyrate in a human pituitary cell line (HP75). Endocrine 22:285–292

    Article  PubMed  CAS  Google Scholar 

  • Larsson O, Wahlestedt C, Timmons JA (2005) Considerations when using the significance analysis of microarrays (SAM) algorithm. BMC Bioinformatics 6:129

    Article  PubMed  Google Scholar 

  • Li CJ, DePamphilis ML (2002) Mammalian Orc1 protein is selectively released from chromatin and ubiquitinated during the S-to-M transition in the cell division cycle. Mol Cell Biol 22:105–116

    Article  PubMed  Google Scholar 

  • Li CJ, Elsasser TH (2005) Butyrate-induced apoptosis and cell cycle arrest in bovine kidney epithelial cells: involvement of caspase and proteasome pathways. J Anim Sci 83:89–97

    PubMed  CAS  Google Scholar 

  • Li CJ, Elsasser TH (2006) Specific cell cycle synchronization with butyrate and cell cycle analysis by flow cytometry for Madin Darby Bovine Kidney (MDBK) cell line. J Anim Vet Adv 5(11):916–923

    Google Scholar 

  • Li RW, Li CJ (2006) Butyrate induces profound changes in gene expression related to multiple signal pathways in bovine kidney epithelial cells. BMC Genomics 7:234

    Article  PubMed  Google Scholar 

  • Li CJ, Vassilev A, DePamphilis ML (2004) Role for Cdk1 (Cdc2)/cyclin A in preventing the mammalian origin recognition complex’s largest subunit (Orc1) from binding to chromatin during mitosis. Mol Cell Biol 24:5875–5886

    Article  PubMed  CAS  Google Scholar 

  • Li RW, Meyer MJ, Van Tassell CP, Sonstegard TS, Connor EE, Van Amburgh ME, Boisclair YR, Capuco AV (2006) Identification of estrogen-responsive genes in the parenchyma and fat pad of the bovine mammary gland by microarray analysis. Physiol Genomics 27:42–53

    Article  PubMed  CAS  Google Scholar 

  • Mayburd AL, Martlinez A, Sackett D, Liu H, Shih J et al (2006) Ingenuity network-assisted transcription profiling: identification of a new pharmacologic mechanism for MK886. Clin Cancer Res 12:1820–1827

    Article  PubMed  CAS  Google Scholar 

  • Myzak MC, Dashwood RH (2006) Histone deacetylases as targets for dietary cancer preventive agents: lessons learned with butyrate, diallyl disulfide, and sulforaphane. Current Drug Targets 7:443–452

    Article  PubMed  CAS  Google Scholar 

  • Myzak MC, Ho E, Dashwood RH (2006) Dietary agents as histone deacetylase inhibitors. Mol Carcinog 45:443–446

    Article  PubMed  CAS  Google Scholar 

  • Pospisil P, Iyer LK, Adelstein SJ, Kassis AI (2006) A combined approach to data mining of textual and structured data to identify cancer-related targets. BMC Bioinformatics 7:354

    Article  PubMed  Google Scholar 

  • Scheppach W, Bartram HP, Richter F (1995) Role of short-chain fatty acids in the prevention of colorectal cancer. Eur J Cancer 31A:1077–1080

    Article  PubMed  CAS  Google Scholar 

  • Shi SL, Wang YY, Liang Y, Li QF (2006) Effects of tachyplesin and n-sodium butyrate on proliferation and gene expression of human gastric adenocarcinoma cell line BGC-823. World J Gastroenterol 12:1694–1698

    PubMed  CAS  Google Scholar 

  • Singh-Gasson S, Green RD, Yue Y, Nelson C, Blattner F et al (1999) Maskless fabrication of light-directed oligonucleotide microarrays using a digital micromirror array. Nat Biotechnol 17:974–978

    Article  PubMed  CAS  Google Scholar 

  • Soulitzis N, Karyotis I, Delakas D, Spandidos DA (2006) Expression analysis of peptide growth factors VEGF, FGF2, TGFB1, EGF and IGF1 in prostate cancer and benign prostatic hyperplasia. Int J Oncol 29:305–314

    PubMed  CAS  Google Scholar 

  • Su YQ, Sugiura K, Woo Y, Wigglesworth K, Kamdar S et al (2006) Selective degradation of transcripts during meiotic maturation of mouse oocytes. Dev Biol 2006 Sep 12; [Epub ahead of print] PMID: 17022963

  • Tabuchi Y, Takasaki I, Doi T, Ishii Y, Sakai H et al (2006) Genetic networks responsive to sodium butyrate in colonic epithelial cells. FEBS Lett 580:3035–3041

    Article  PubMed  CAS  Google Scholar 

  • Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116–5121

    Article  PubMed  CAS  Google Scholar 

  • Vozenin-Brotons MC, Gault N, Sivan V, Tricaud Y, Dubray B et al (1999) Histopathological and cellular studies of a case of cutaneous radiation syndrome after accidental chronic exposure to a cesium source. Radiat Res 152:332–337

    Article  PubMed  CAS  Google Scholar 

  • Watson AJ (2006) An overview of apoptosis and the prevention of colorectal cancer. Crit Rev Oncol Hematol 57:107–121

    PubMed  Google Scholar 

  • Williams AC, Smartt H, AM HZ, Macfarlane M, Paraskeva C et al (2006) Insulin-like growth factor binding protein 3 (IGFBP-3) potentiates TRAIL-induced apoptosis of human colorectal carcinoma cells through inhibition of NF-kappaB. Cell Death Differ advance online publication, 28 April 2006; doi: 10.1038/sj.cdd.4401919

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Authors and Affiliations

  1. Growth Biology Laboratory, Animal and Natural Resources Institute, ARS, USDA, 10300 Baltimore Avenue, Building 200, Room 209, BARC East, Beltsville, MD, 20705, USA

    Cong-jun Li & Ted H. Elsasser

  2. Bovine Functional Genomic Laboratory, Animal and Natural Resources Institute, ARS, USDA, B.A.R.C. East, Beltsville, MD, 20705, USA

    Robert W Li

  3. SAIC-Frederick, NCI-Frederick, Frederick, MD, USA

    Yong-hong Wang

Authors
  1. Cong-jun Li
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  2. Robert W Li
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  3. Yong-hong Wang
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  4. Ted H. Elsasser
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Correspondence to Cong-jun Li.

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Mention of trade names or commercial products in this publication is solely for providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture.

Electronic supplementary material

Below is the link to the electronic supplementary material:

Electronic Supplementary Material Table S1

List of Focus genes (DOC 268 KB)

Electronic Supplemental Material Table S2

Global Functional Analysis. major functions and genes involved (DOC 50.0 KB)

Electronic Supplementary Material Table S3

List of up-regulated genetic networks (DOC 31.0 KB)

Electronic Supplemental Material Table S4

List of down-regulated genetic networks (DOC 34.5 KB)

Electronic Supplemental Materials Table S5

Integrated Genomic Networks (DOC 43.0 KB)

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Li, Cj., Li, R.W., Wang, Yh. et al. Pathway analysis identifies perturbation of genetic networks induced by butyrate in a bovine kidney epithelial cell line. Funct Integr Genomics 7, 193–205 (2007). https://doi.org/10.1007/s10142-006-0043-2

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  • DOI: https://doi.org/10.1007/s10142-006-0043-2

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