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

Kenzo Soejima, Weizhao Fang, Barrett J. Rollins

Research output: Contribution to journalArticle

74 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4723-4733
Number of pages11
JournalOncogene
Volume22
Issue number30
DOIs
Publication statusPublished - 2003 Jul 24
Externally publishedYes

Fingerprint

Agar
Antigens
Viral Tumor Antigens
Methyltransferases
DNA Methylation
Tumor Suppressor Genes
Fibroblasts
Epithelial Cells
Polyomavirus Transforming Antigens
Telomerase
DNA
Genetic Promoter Regions
Methylation
Chromatin
Lung Neoplasms
Down-Regulation
Embryonic Structures
Phenotype
DNA methyltransferase 3B
Growth

Keywords

  • DNA methyltransferase
  • Lung cancer
  • Tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras. / Soejima, Kenzo; Fang, Weizhao; Rollins, Barrett J.

In: Oncogene, Vol. 22, No. 30, 24.07.2003, p. 4723-4733.

Research output: Contribution to journalArticle

Soejima, Kenzo ; Fang, Weizhao ; Rollins, Barrett J. / DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40T antigen and activated Ras. In: Oncogene. 2003 ; Vol. 22, No. 30. pp. 4723-4733.
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