Epigenetic silencing of multiple interferon pathway genes after cellular immortalization.
Abrogating cellular senescence is a necessary step in the formation of a cancer cell. Promoter hypermethylation is an epigenetic mechanism of gene regulation known to silence gene expression in carcinogenesis. Treatment of spontaneously immortal Li-Fraumeni fibroblasts with 5-aza-2'-deoxycytidine (5AZA-dC), an inhibitor of DNA methyltransferase (DNMT), induces a senescence-like state. We used microarrays containing 12 558 genes to determine the gene expression profile associated with cellular immortalization and also regulated by 5AZA-dC. Remarkably, among 85 genes with methylation-dependent downregulation (silencing) after immortalization, 39 (46%) are known to be regulated during interferon signaling, a known growth-suppressive pathway. This work indicates that gene silencing may be associated with an early event in carcinogenesis, cellular immortalization.
Kulaeva
Olga I
OI
Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 110 Warren Ave., Detroit, MI 48201, USA.
Draghici
Sorin
S
Tang
Lin
L
Kraniak
Janice M
JM
Land
Susan J
SJ
Tainsky
Michael A
MA
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002455:Cell Division; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007372:Interferons / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D010641:Phenotype; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; D009841:Oligonucleotides; D000077209:Decitabine; D007372:Interferons; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine