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Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Oncogene volume 26, pages 5553–5563 (2007)Cite this article

Abstract

Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal DNA methylation patterns of cancer cells are established and maintained. Here, we identify over 20 DNMT3B transcripts from many cancer cell lines and primary acute leukemia cells that contain aberrant splicing at the 5′ end of the gene, encoding truncated proteins lacking the C-terminal catalytic domain. Many of these aberrant transcripts retain intron sequences. Although the aberrant transcripts represent a minority of the DNMT3B transcripts present, Western blot analysis demonstrates truncated DNMT3B isoforms in the nuclear protein extracts of cancer cells. To test if expression of a truncated DNMT3B protein could alter the DNA methylation patterns within cells, we expressed DNMT3B7, the most frequently expressed aberrant transcript, in 293 cells. DNMT3B7-expressing 293 cells have altered gene expression as identified by microarray analysis. Some of these changes in gene expression correlate with altered DNA methylation of corresponding CpG islands. These results suggest that truncated DNMT3B proteins could play a role in the abnormal distribution of DNA methylation found in cancer cells.

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Acknowledgements

We thank Hongwei Zou and Wai Hui for technical assistance; Dr Gregory L Shipley of the Quantitative Genomics Core Laboratory at The University of Texas at Houston Health Science Center for developing and running the real-time PCR assays; Dr Xinmin Li and Jean Shi for assistance with microarray analysis; Dr Shang Lin for assistance with statistical analysis; and Drs Charles Rudin, Michael Nishimura, Suzanne Conzen, and Michael Thirman for gifts of cell lines. We thank Drs Stephen B Baylin, Kevin Shannon, Anthony Fernald, Yanwen Jiang, John Joslin and Dr Zhijian Qian for their contributions to the data presented and their thoughtful comments regarding this work. This work was funded by a Howard Hughes Postdoctoral Fellowship, the University of Chicago Section of Hematology/Oncology Fund-a-Fellow Program, a Cancer Research Foundation Young Investigator Award, an American Society of Clinical Oncology Young Investigator Award, an American Cancer Society Institutional Research Grant IRG-58-004-44, a Schweppe Foundation Career Development Award and The Kimmel Scholar Award (LA Godley), and by NIH grant CA 40046 (MM Le Beau).

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  1. S L Payne

    Present address: 3Current address: Department of Biology, Elmhurst College, 190 Prospect Ave., Elmhurst, IL 60126, USA.,

Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

    K R Ostler, E M Davis, S L Payne, B B Gosalia, J Expósito-Céspedes, M M Le Beau & L A Godley

  2. University of Chicago Cancer Research Center, University of Chicago, Chicago, IL, USA

    M M Le Beau & L A Godley

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  1. K R Ostler
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Correspondence to L A Godley.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Ostler, K., Davis, E., Payne, S. et al. Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 26, 5553–5563 (2007). https://doi.org/10.1038/sj.onc.1210351

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