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  • Original Paper
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DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras

Oncogene volume 22, pages 4723–4733 (2003)Cite this article

Abstract

Transcriptional silencing of tumor suppressor genes in association with DNA methylation contributes to malignant transformation. However, the specific DNA methyltransferases that initiate this process are unknown. Here we show that a de novo DNA methyltransferase, DNMT3b, substantially contributes to the oncogenic phenotype in a lung cancer model. Normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and activated Ras were immortal, formed colonies in soft agar, and expressed DNMT3b. Antisense suppression of DNMT3b prevented soft agar growth. Furthermore, mouse embryo fibroblasts expressing T antigen and Ras formed soft agar colonies and large tumors, but fibroblasts from Dnmt3b−/− mice did not grow in soft agar and were much less tumorigenic in vivo. The tumor suppressor genes, FHIT, TSLC1, and RASSF1A were downregulated in transformed NHBE cells, and antisense DNMT3b treatment resulted in re-expression of FHIT and TSLC1. While expression of TSCL1 correlated with methylation of CpG dinucleotides in its promoter region, the expression of FHIT did not, suggesting that DNMT3b may silence genes by several mechanisms including direct DNA methylation or recruitment of proteins that modify chromatin. Regardless of mechanism, our data indicate that DNMT3b plays an important role in transformation.

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Acknowledgements

We thank Drs En Li and Masaki Okano for Dnmt3b−/− MEFs and advice; Drs James DeCaprio, Matthew Meyerson, Jeong Wu Lee, Takahiro Arai, Seitaro Fujishima, and Chiaki Takahashi for reagents and helpful comments; and Christine Penta for administrative assistance. The work was supported by the Novartis/Dana-Farber Drug Discovery Program (BJR), and the Uehara Memorial Foundation (KS).

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  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, MA, USA

    Kenzo Soejima, Weizhao Fang & Barrett J Rollins

  2. Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, 02115, MA, USA

    Kenzo Soejima, Weizhao Fang & Barrett J Rollins

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  1. Kenzo Soejima
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  2. Weizhao Fang
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Correspondence to Barrett J Rollins.

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Soejima, K., Fang, W. & Rollins, B. DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras. Oncogene 22, 4723–4733 (2003). https://doi.org/10.1038/sj.onc.1206510

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