title: Oncogenic role of PDK4 in human colon cancer cells.
abstract: BACKGROUND
  Cancer cells maintain high rates of glycolysis. Pyruvate dehydrogenase kinases (PDK) contribute to this phenomenon, which favours apoptosis resistance and cellular transformation. We previously reported upregulation of PDK4 in normal mucosa of colorectal cancer (CRC) patients compared with controls and in preneoplastic intestine of our mouse model. Decreased methylation of four consecutive PDK4 CpGs was observed in normal mucosa of patients. Although other members of the PDK family have been investigated for transformation potential, PDK4 has not been extensively studied.
  
  
  METHODS
  PDK4 methylation in blood of CRC patients and controls was evaluated by pyrosequencing. PDK4 expression in human colon carcinoma cells was down-regulated by RNAi. Cellular migration and invasion, apoptosis and qRT-PCR of key genes were assessed.
  
  
  RESULTS
  Pyrosequencing revealed decreased methylation of the same four consecutive CpGs in the blood of patients compared with controls. Cellular migration and invasion were reduced and apoptosis was increased following transient or stable inhibition of PDK4. Expression of vimentin, HIF-1 and VEGFA was reduced.
  
  
  CONCLUSIONS
  These studies demonstrate the involvement of PDK4 in transformation. Methylation assessment of PDK4 in the blood may be useful for non-invasive CRC detection. PDK4 should be considered as a target for development of anticancer strategies and therapies.
authors.affiliation: Department of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Decarie Boulevard, Room E.M0.3211, Montreal, QC H4A 3J1, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Leclerc
authors.affiliation: Department of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Decarie Boulevard, Room E.M0.3211, Montreal, QC H4A 3J1, Canada.
authors.forename: D N T
authors.initials: DN
authors.lastname: Pham
authors.affiliation: Department of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Decarie Boulevard, Room E.M0.3211, Montreal, QC H4A 3J1, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Lévesque
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Truongcao
authors.affiliation: Department of Medical Genetics, The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.|Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.|Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: W D
authors.initials: WD
authors.lastname: Foulkes
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sapienza
authors.affiliation: Department of Human Genetics and Pediatrics, The Research Institute of the McGill University Health Centre, McGill University, 1001 Decarie Boulevard, Room E.M0.3211, Montreal, QC H4A 3J1, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases