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    Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP-3B/GDF10) in lung cancer cells

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    Authors
    Tandon, Manish
    Gokul, Karthiga Devi
    Ali, Syed A.
    Chen, Zujian
    Lian, Jane B.
    Stein, Gary S.
    Pratap, Jitesh
    UMass Chan Affiliations
    Department of Cell Biology
    Document Type
    Journal Article
    Publication Date
    2012-06-18
    Keywords
    Core Binding Factor Alpha 1 Subunit
    Bone Morphogenetic Protein 3
    Lung Neoplasms
    Cancer Biology
    Cell and Developmental Biology
    Life Sciences
    Medicine and Health Sciences
    
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    Abstract
    BACKGROUND: The Runt-related transcription factor Runx2 is essential for bone development but is also implicated in progression of several cancers of breast, prostate and bone, where it activates cancer-related genes and promotes invasive properties. The transforming growth factor beta (TGF-beta) family member bone morphogenetic protein-3B (BMP-3B/GDF10) is regarded as a tumor growth inhibitor and a gene silenced in lung cancers; however the regulatory mechanisms leading to its silencing have not been identified. RESULTS: Here we show that Runx2 is highly expressed in lung cancer cells and downregulates BMP-3B. This inverse relationship between Runx2 and BMP-3B expression is further supported by increased expression of BMP-3B in mesenchymal cells from Runx2 deficient mice. The ectopic expression of Runx2, but not DNA binding mutant Runx2, in normal lung fibroblast cells and lung cancer cells resulted in suppression of BMP-3B levels. The chromatin immunoprecipitation studies identified that the mechanism of Runx2-mediated suppression of BMP-3B is due to the recruitment of Runx2 and histone H3K9-specific methyltransferase Suv39h1 to BMP-3B proximal promoter and a concomitant increase in histone methylation (H3K9) status. The knockdown of Runx2 in H1299 cells resulted in decreased histone H3K9 methylation on BMP-3B promoter and increased BMP-3B expression levels. Furthermore, co-immunoprecipitation studies showed a direct interaction of Runx2 and Suv39h1 proteins. Phenotypically, Runx2 overexpression in H1299 cells increased wound healing response to TGFbeta treatment. CONCLUSIONS: Our studies identified BMP-3B as a new Runx2 target gene and revealed a novel function of Runx2 in silencing of BMP-3B in lung cancers. Our results suggest that Runx2 is a potential therapeutic target to block tumor suppressor gene silencing in lung cancer cells.
    Source
    Mol Cancer. 2012 Jun 18;11:27. Link to article on publisher's site 2012 Tandon et al.; licensee BioMed Central Ltd.
    DOI
    10.1186/1476-4598-11-27
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/39527
    PubMed ID
    22537242
    Related Resources
    Link to Article in PubMed
    Rights
    © 2012 Tandon et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    ae974a485f413a2113503eed53cd6c53
    10.1186/1476-4598-11-27
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