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Carcinogenesis Advance Access published online on October 21, 2004
Carcinogenesis, doi:10.1093/carcin/bgh318
© 2004 by Oxford University Press
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Received August 18, 2004
Revised October 8, 2004
Accepted October 12, 2004

CARCINOGENESIS

Oncogene regulation of tumor suppressor genes in tumorigenesis

Jimmy Sung 1, Joel Turner 1, Susan McCarthy 1, Steve Enkemann 1, Chan Gong Li 1, Perally Yan 1, Timothy Huang 1, and Timothy J. Yeatman 1*

1 Department of Surgery and Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa FL 33612, USA; Department of Molecular Virology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA

* To whom correspondence should be addressed.
Timothy J. Yeatman, E-mail: yeatman{at}moffitt.usf.edu


  Abstract

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 3Y1 mock-transfected versus v-src transfected rat fibroblasts identified significant over-expression of DNA methyltransferase 1 (dnmt1), 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 (DAC), a potent de-methylating 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.

Keywords: Oncogenes; methylation; epigenetics; tumor suppressor gene.
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