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Cancer Cell. 2014 Oct 13;26(4):577-90. doi: 10.1016/j.ccr.2014.07.028. Epub 2014 Sep 25.

Gene body methylation can alter gene expression and is a therapeutic target in cancer.

Author information

1
Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
2
The Princess Margaret Cancer Centre, University Health Network, Toronto ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto ON M5G 2M9, Canada.
3
Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: pjones@med.usc.edu.
4
Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: gliang@usc.edu.

Abstract

DNA methylation in promoters is well known to silence genes and is the presumed therapeutic target of methylation inhibitors. Gene body methylation is positively correlated with expression, yet its function is unknown. We show that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the overexpression of genes, many of which are involved in metabolic processes regulated by c-MYC. Downregulation is caused by DNA demethylation of the gene bodies and restoration of high levels of expression requires remethylation by DNMT3B. Gene body methylation may, therefore, be an unexpected therapeutic target for DNA methylation inhibitors, resulting in the normalization of gene overexpression induced during carcinogenesis. Our results provide direct evidence for a causal relationship between gene body methylation and transcription.

PMID:
25263941
PMCID:
PMC4224113
DOI:
10.1016/j.ccr.2014.07.028
[Indexed for MEDLINE]
Free PMC Article

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