title: Unique methylation pattern of oncostatin m receptor gene in cancers of colorectum and other digestive organs.
abstract: OBJECTIVE
  Oncostatin M (OSM) is an interleukin-6 cytokine family member, which inhibits cell proliferation and induces cell differentiation and apoptosis in cancers. In melanoma cells, epigenetic silencing of OSM receptor (OSMR) by histone deacetylation contributes to escape of cell growth control by OSM. However, the silencing of OSMR by DNA methylation in any cancer has not been examined.
  
  
  METHODS
  Methylation status of OSMR was determined by sequencing or methylation-specific PCR in primary tumors and cell lines. Cell lines were treated with DNA methyltransferase inhibitors 5-aza-2-deoxycytidine or DNA methyltransferase 1 small interfering RNA or a histone deacetylase inhibitor trichostatin A. OSMR mRNA level was determined by reverse transcription-PCR. The acetylation of histone H3 was analyzed by chromatin immunoprecipitation assay.
  
  
  RESULTS
  We observed methylation of OSMR in 88 of 98 (90%) colorectal cancers, 34 of 38 (89%) colorectal polyps, 17 of 31 (55%) normal-appearing mucosa adjacent to colorectal cancers, 13 of 40 (33%) gastric cancers, and 2 of 10 (20%) pancreatic cancers. OSMR methylation was absent or rarely detected in normal colonic mucosa from noncancer patients or in cancers of nondigestive organs, including breast, lung, liver, prostate, kidney, and melanoma. We observed a significant correlation between OSMR methylation and loss of mRNA expression in 39 cancer cell lines. Following the treatment of colorectal cancer cell lines with 5-aza-2-deoxycytidine, DNA methyltransferase 1 small interfering RNA, or trichostatin A, the induction of OSMR mRNA and the enrichment in the level of histone acetylation were observed.
  
  
  CONCLUSIONS
  The epigenetic silencing and DNA methylation of OSMR occur frequently in colorectal cancers and rarely in cancers of nondigestive organs. OSMR methylation is an early event in the colorectal carcinogenesis.
authors.affiliation: Gastrointestinal Research Laboratory (151M2), Veteran Affairs Medical Center of San Francisco, Department of Medicine, University of California San Franicisco, San Francisco, CA 94121, USA. guoren.deng@ucsf.edu
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kakar
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okudiara
authors.forename: Esther
authors.initials: E
authors.lastname: Choi
authors.forename: Marvin H
authors.initials: MH
authors.lastname: Sleisenger
authors.forename: Young S
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000235:genetics; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D041981:Gastrointestinal Tract / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D000077209:Decitabine; D015254:DNA Modification Methylases; D006655:Histone Deacetylases; D001374:Azacitidine