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  • Oncogenomics
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Epigenetic silencing of multiple interferon pathway genes after cellular immortalization

Oncogene volume 22, pages 4118–4127 (2003)Cite this article

Abstract

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.

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Acknowledgements

This work was supported by the Barbara and Fred Erb Endowed Chair in Cancer Genetics to MAT, funds from the Karmanos Cancer Institute, the State of Michigan Life Sciences Corridor, the Molecular Medicine and Genetics Applied Genomics Technology Center at WSU, and the Genomics Core of the Karmanos Cancer Institute, P30CA022453. We acknowledge helpful comments on this manuscript from Vasily Studitsky, Aviva Fridman, George Brush; the assistance of Tara Twomey and Purvesh Khatri is greatly appreciated (Wayne State University). Also, we acknowledge Dr Bruce Hoff for helpful advice (BioDiscovery) and Dr Douglas Leaman for providing interferon gene expression data prior to publication. This work has been supported in part by grants to SD from the National Science Foundation grant number 0234806 and Department of Defense grant number DAMD17-03-2-0035.

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Author notes

  1. Olga I Kulaeva and Sorin Draghici: These two authors contributed substantially to this work and both should be considered as first authors.

Authors and Affiliations

  1. Barbara Ann Karmanos Cancer Institute, and Department of Pathology, Wayne State University School of Medicine, 110 Warren Ave., Detroit, 48201, MI, USA

    Olga I Kulaeva, Lin Tang, Janice M Kraniak & Michael A Tainsky

  2. Wayne State University, 5143 Cass Ave., Rm. 408, Detroit, 48202, MI, USA

    Sorin Draghici

  3. Molecular Medicine and Genetics, Wayne State University, 5107 Biological Sciences Bldg., Detroit, 48202, MI, USA

    Susan J Land & Michael A Tainsky

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  1. Olga I Kulaeva
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  2. Sorin Draghici
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Correspondence to Michael A Tainsky.

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Kulaeva, O., Draghici, S., Tang, L. et al. Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene 22, 4118–4127 (2003). https://doi.org/10.1038/sj.onc.1206594

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