Research Papers:

DNA-intercalators Causing Rapid Re-expression of Methylated and Silenced Genes in Cancer Cells

M. Zulfiquer Hossain, Megan A. Healey, Calvin Lee, Weijie Poh, Sashidhar R. Yerram, Kalpesh Patel, Nilofer S. Azad, James G. Herman and Scott E. Kern _

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Oncotarget. 2012; 4:298-309. https://doi.org/10.18632/oncotarget.863

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M. Zulfiquer Hossain1, Megan A. Healey1, Calvin Lee1, Weijie Poh1, Sashidhar R. Yerram1, Kalpesh Patel1, Nilofer S. Azad1, James G. Herman1, and Scott E. Kern1

1 Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland


Scott E. Kern, email:

Keywords: cancer, gene methylation, demethylation, DNA-intercalator, quinacrine, DNMT inhibitor, epigenetics, silencing and re-activation of gene expression, small molecule-DNA interactions

Received: February 8, 2013 Accepted: February 25, 2013 Published: February 26, 2013


Epigenetic inactivation of tumor-suppressor and other regulatory genes plays a critical role in carcinogenesis. Transcriptional silencing is often maintained by DNA methyl transferase (DNMT)-mediated hypermethylation of CpG islands in promoter DNA. Nucleoside analogs including azacytidine and decitabine have been used to inhibit DNMT and re-activate genes, and are clinically used. Their shortcomings include a short half-life and a slow onset of action due to required nucleotide incorporation during DNA replication, which may limit clinical utility. It might be useful to begin to identify lead compounds having novel properties, specifically distinct and fast-acting gene desilencing. We previously identified chemicals augmenting gene expression in multiple reporter systems. We now report that a subset of these compounds that includes quinacrine re-expresses epigenetically silenced genes implicated in carcinogenesis. p16, TFPI2, the cadherins E-cadherin and CDH13, and the secreted frizzle-related proteins (SFRPs) SFRP1 and SFRP5 were desilenced in cancer cell lines. These lead compounds were fast-acting: re-expression occurred by 12-24 hours. Re-activation of silenced genes was accompanied by depletion of DNMT1 at the promoters of activated genes and demethylation of DNA. A model compound, 5175328, induced changes more rapidly than decitabine. These gene desilencing agents belonged to a class of acridine compounds, intercalated into DNA, and inhibited DNMT1 activity in vitro. Although to define the mechanism would be outside the scope of this initial report, this class may re-activate silenced genes in part by intercalating into DNA and subsequently inhibiting full DNMT1 activity. Rapid mechanisms for chemical desilencing of methylated genes therefore exist.

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