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Symmetric dimeric bisbenzimidazoles DBP(n) reduce methylation of RARB and PTEN while significantly increase methylation of rRNA genes in MCF-7 cancer cells.

Abstract

BACKGROUND

Hypermethylation is observed in the promoter regions of suppressor genes in the tumor cancer cells. Reactivation of these genes by demethylation of their promoters is a prospective strategy of the anticancer therapy. Previous experiments have shown that symmetric dimeric bisbenzimidazoles DBP(n) are able to block DNA methyltransferase activities. It was also found that DBP(n) produces a moderate effect on the activation of total gene expression in HeLa-TI population containing epigenetically repressed avian sarcoma genome.

PRINCIPAL FINDINGS

It is shown that DBP(n) are able to penetrate the cellular membranes and accumulate in breast carcinoma cell MCF-7, mainly in the mitochondria and in the nucleus, excluding the nucleolus. The DBP(n) are non-toxic to the cells and have a weak overall demethylation effect on genomic DNA. DBP(n) demethylate the promoter regions of the tumor suppressor genes PTEN and RARB. DBP(n) promotes expression of the genes RARB, PTEN, CDKN2A, RUNX3, Apaf-1 and APC "silent" in the MCF-7 because of the hypermethylation of their promoter regions. Simultaneously with the demethylation of the DNA in the nucleus a significant increase in the methylation level of rRNA genes in the nucleolus was detected. Increased rDNA methylation correlated with a reduction of the rRNA amount in the cells by 20-30%. It is assumed that during DNA methyltransferase activity inhibition by the DBP(n) in the nucleus, the enzyme is sequestered in the nucleolus and provides additional methylation of the rDNA that are not shielded by DBP(n).

CONCLUSIONS/SIGNIFICANCE

It is concluded that DBP (n) are able to accumulate in the nucleus (excluding the nucleolus area) and in the mitochondria of cancer cells, reducing mitochondrial potential. The DBP (n) induce the demethylation of a cancer cell's genome, including the demethylation of the promoters of tumor suppressor genes. DBP (n) significantly increase the methylation of ribosomal RNA genes in the nucleoli. Therefore the further study of these compounds is needed; it could lead to the creation of new anticancer agents.

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  • Authors+Show Affiliations

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    Research Centre for Medical Genetics, Moscow, Russia.

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    Chemistry Department, Moscow State University, Moscow, Russia.

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    Chemistry Department, Moscow State University, Moscow, Russia.

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    Chemistry Department, Moscow State University, Moscow, Russia.

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    Research Centre for Medical Genetics, Moscow, Russia.

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    Research Centre for Medical Genetics, Moscow, Russia.

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    Research Centre for Medical Genetics, Moscow, Russia.

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    N.N. Blokhin Russian Cancer Research Center, Moscow, Russia.

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    Engelhardt Institute of Molecular Biology, Moscow, Russia.

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    Engelhardt Institute of Molecular Biology, Moscow, Russia.

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    Chemistry Department, Moscow State University, Moscow, Russia.

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    I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia. P.K. Anokhin Institute of Normal Physiology, Moscow, Russia.

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    Chemistry Department, Moscow State University, Moscow, Russia.

    Chemistry Department, Moscow State University, Moscow, Russia.

    Source

    PloS one 13:1 2018 pg e0189826

    MeSH

    Benzimidazoles
    DNA Methylation
    Dimerization
    HeLa Cells
    Humans
    MCF-7 Cells
    PTEN Phosphohydrolase
    RNA, Ribosomal
    Reactive Oxygen Species
    Receptors, Retinoic Acid

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    29329300