Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma.
We performed a comprehensive survey of commonly inactivated tumor suppressor genes in esophageal squamous cell carcinoma (ESCC) based on functional reactivation of epigenetically silenced tumor suppressor genes by 5-aza-2'-deoxycytidine and trichostatin A using microarrays containing 12599 genes. Among 58 genes identified by this approach, 44 (76%) harbored dense CpG islands in the promoter regions. Thirteen of twenty-two tested gene promoters were methylated in cell lines, and ten in primary ESCC accompanied by silencing at the mRNA level. Potent growth suppressive activity of three genes including CRIP-1, Apolipoprotein D, and Neuromedin U in ESCC cells was demonstrated by colony focus assays. Pharmacologic reversal of epigenetic silencing is a powerful approach for comprehensive identification of tumor suppressor genes in human cancers.
Yamashita
Keishi
K
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, 720 Rutland Avenue, Ross Building 818, Baltimore, MD 21205, USA.
Upadhyay
Sunil
S
Osada
Motonobu
M
Hoque
Mohammad O
MO
Xiao
Yan
Y
Mori
Masaki
M
Sato
Fumiaki
F
Meltzer
Stephen J
SJ
Sidransky
David
D
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine