Oncogene regulation of tumor suppressor genes in tumorigenesis.
We attempted to demonstrate whether there is an epigenetic link between oncogenes and tumor suppression genes in tumorigenesis. We designed a high throughput model to identify a candidate group of tumor suppressor genes potentially regulated by oncogenes. Gene expression profiling of mock-transfected versus v-src-transfected 3Y1 rat fibroblasts identified significant overexpression of DNA methyltransferase 1, the enzyme responsible for aberrant genome methylation, in v-src-transfected fibroblasts. Secondary microarray analyses identified a number of candidate tumor suppressor genes that were down-regulated by v-src but were also re-expressed following treatment with 5-aza-2'-deoxycytidine, a potent demethylating agent. This candidate group included both tumor suppressor genes that are known to be silenced by DNA hypermethylation and those that have not been previously identified with promoter hypermethylation. To further validate our model, we identified tsg, a tumor suppressor gene that was shown to be down-regulated by v-src and found to harbor dense promoter hypermethylation. Our model demonstrates a cooperative relationship between oncogenes and tumor suppressor genes mediated through promoter hypermethylation.
Sung
Jimmy
J
Department of Surgery and Interdisciplinary Oncology, H.Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
Turner
Joel
J
McCarthy
Susan
S
Enkemann
Steve
S
Li
Chan Gong
CG
Yan
Perally
P
Huang
Timothy
T
Yeatman
Timothy J
TJ
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000378:metabolism; D000077209:Decitabine; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D016391:Genes, src / Q000235:genetics*; D046228:Microarray Analysis / Q000379:methods; D009857:Oncogenes; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats
D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine