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

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

doi:10.18632/oncotarget.863

Cited by 20 publications

(19 citation statements)

References 44 publications

(51 reference statements)

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“…Multiple structure affinity relationship studies have further demonstrated that flavones are capable of intercalating into DNA duplexes [ 44 , 45 ]. The planarity of the benzopyrone skeleton of flavones allows them to easily intercalate the DNA helixes compared to other less planar and non-polar flavonoids.…”

Section: Discussionmentioning

confidence: 99%

Dietary Flavones as Dual Inhibitors of DNA Methyltransferases and Histone Methyltransferases

et al. 2016

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Methylation of DNA and histone proteins are mutually involved in the epigenetic regulation of gene expression mediated by DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs). DNMTs methylate cytosine residues within gene promoters, whereas HMTs catalyze the transfer of methyl groups to lysine and arginine residues of histone proteins, thus causing chromatin condensation and transcriptional repression, which play an important role in the pathogenesis of cancer. The potential reversibility of epigenetic alterations has encouraged the development of dual pharmacologic inhibitors of DNA and histone methylation as anticancer therapeutics. Dietary flavones can affect epigenetic modifications that accumulate over time and have shown anticancer properties, which are undefined. Through DNA binding and in silico protein-ligand docking studies with plant flavones viz. Apigenin, Chrysin and Luteolin, the effect of flavones on DNA and histone methylation was assessed. Spectroscopic analysis of flavones with calf-thymus DNA revealed intercalation as the dominant binding mode, with specific binding to a GC-rich sequence in the DNA duplex. A virtual screening approach using a model of the catalytic site of DNMT and EZH2 demonstrated that plant flavones are tethered at both ends inside the catalytic pocket of DNMT and EZH2 by means of hydrogen bonding. Epigenetic studies performed with flavones exhibited a decrease in DNMT enzyme activity and a reversal of the hypermethylation of cytosine bases in the DNA and prevented cytosine methylation in the GC-rich promoter sequence incubated with the M.SssI enzyme. Furthermore, a marked decrease in HMT activity and a decrease in EZH2 protein expression and trimethylation of H3K27 were noted in histones isolated from cancer cells treated with plant flavones. Our results suggest that dietary flavones can alter DNMT and HMT activities and the methylation of DNA and histone proteins that regulate epigenetic modifications, thus providing a significant anticancer effect by altering epigenetic processes involved in the development of cancer.

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Section: Discussionmentioning

confidence: 99%

Dietary Flavones as Dual Inhibitors of DNA Methyltransferases and Histone Methyltransferases

et al. 2016

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“…S7). Moreover, DNA methyltransferase 1 (DNMT1) plays an important role in maintaining DNA methylation patterns [25,26], Shukla showed that DNMT1 was a transcriptional target of BRCA1 [27]. Our recent study confirmed that DNMT1 mRNA and protein were decreased in BRCA1 -mutated breast cancer.…”

Section: Discussionmentioning

confidence: 53%

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

Chen

et al. 2014

Oncotarget

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Phosphatidylethanolamine N-methyltransferase (PEMT) plays a critical role in breast cancer progression. However, the epigenetic mechanism regulating PEMT transcription remains largely unknown. Here, we show that the first promoter-specific transcript 1 is the major PEMT mRNA species, and methylation of the -132 site is a key regulatory element for the PEMT gene in BRCA1-mutated breast cancer. Mechanistically, hypermethylated -132 site-mediated loss of active histone marks H3K9ac and increase of repressive histone marks H3K9me enrichment synergistically inhibited PEMT transcription. Clinicopathological data indicated that a hypermethylated -132 site was associated with histological grade (P = 0.031) and estrogen receptor status (P = 0.004); univariate survival and multivariate analyses demonstrated that lymph node metastasis was an independent and reliable prognostic factor for BRCA1-mutated breast cancer patients. Our findings imply that genetic (e.g., BRCA1 mutation) and epigenetic mechanisms (e.g., DNA methylation and histone modifications) are jointly involved in the malignant progression of PEMT-related breast cancer.

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“…70 To develop DNA ligands as inhibitors of DNA methylation, it is important to keep in mind the need for selectivity towards CpG islands and, ideally, tumor suppressor promoters that are hypermethylated in cancer. Compound 7 (Figure 2) was rationally designed from a family of minor groove binders.…”

Section: / Update On the Identified Inhibitorsmentioning

confidence: 99%

Targeting DNA Methylation with Small Molecules: What’s Next?

et al. 2014

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DNA methylation is a mammalian epigenetic mark that is involved in defining where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumor suppressor genes, and by reactivating other regions, such as repeated elements, it is a promising therapeutic target. Two compounds are already approved to treat hematological cancers. Many efforts have been carried out to discover new molecules that are able to efficiently inhibit DNA methylation in cancer cells. We will briefly overview the foremost of these efforts by focusing on what we have learned to this point on non-nucleoside inhibitors and on what we consider to be the features of an ideal inhibitor.

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

Cited by 20 publications

References 44 publications

Dietary Flavones as Dual Inhibitors of DNA Methyltransferases and Histone Methyltransferases

Dietary Flavones as Dual Inhibitors of DNA Methyltransferases and Histone Methyltransferases

Epigenetic repression of phosphatidylethanolamineN-methyltransferase (PEMT) inBRCA1-mutated breast cancer

Targeting DNA Methylation with Small Molecules: What’s Next?

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