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Treatment of breast cancer cells with DNA demethylating agents leads to a release of Pol II stalling at genes with DNA-hypermethylated regions upstream of TSS

  1. Author:
    Tao, Y. G.
    Liu, S.
    Briones, V.
    Geiman, T. M.
    Muegge, K.

  2. Author Address

    [Tao, Yongguang; Briones, Victorino; Geiman, Theresa M.; Muegge, Kathrin] NCI, Lab Canc Prevent, SAIC Frederick, Frederick, MD 21701 USA. [Tao, Yongguang] Cent S Univ, Xiangya Sch Med, Canc Res Inst, Changsha 410078, Hunan, Peoples R China. [Liu, Shuang] NCI, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21701 USA.;Muegge, K (reprint author), NCI, Lab Canc Prevent, SAIC Frederick, Frederick, MD 21701 USA;Kathrin.Muegge@nih.gov
    1. Year: 2011
    2. Date: Dec
  2. Journal: Nucleic Acids Research
    1. 39
    2. 22
    3. Pages: 9508-9520
  4. Type of Article: Article
  5. ISSN: 0305-1048
  1. Abstract:

    Inactivation of tumor suppressor genes plays an important role in tumorigenesis, and epigenetic modifications such as DNA methylation are frequently associated with transcriptional repression. Here, we show that gene silencing at selected genes with signs of DNA hypermethylation in breast cancer cells involves Pol II stalling. We studied several repressed genes with DNA hypermethylation within a region 1-kb upstream of the transcriptional start site that were upregulated after treatment with DNA demethylating agents, such as Azacytidine and several natural products. All those selected genes had stalled Pol II at their transcriptional start site and showed enhanced ser2 phosphorylated Pol II and elevated transcripts after drug treatment indicating successful elongation. In addition, a decrease of the epigenetic regulator LSH in a breast cancer cell line by siRNA treatment reduced DNA methylation and overcame Pol II stalling, whereas overexpression of LSH in a normal breast epithelial cell line increased DNA methylation and resulted in repression. Decrease of LSH was associated with reduced DNMT3b binding to promoter sequences, and depletion of DNMT3b by siRNA could release Pol II suggesting that DNMT3b is functionally involved. The release of paused Pol II was accompanied by a dynamic switch from repressive to active chromatin marks. Thus release of Pol II stalling can act as a mechanism for gene reactivation at specific target genes after DNA demethylating treatment in cancer cells.

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External Sources

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  2. DOI: 10.1093/nar/gkr611
  3. View record in Web of Science®
  4. WOS: 000298186000012

Library Notes

  1. Fiscal Year: FY2011-2012
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