title: Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP-3B/GDF10) in lung cancer cells.
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 β (TGF-β) 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 TGFβ 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.
authors.affiliation: Department of Anatomy and Cell Biology, Rush University Medical Center, Armour Academic Center, 600 S, Paulina St, Suite 507, Chicago, IL, 60612, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Tandon
authors.forename: Karthiga
authors.initials: K
authors.lastname: Gokul
authors.forename: Syed A
authors.initials: SA
authors.lastname: Ali
authors.forename: Zujian
authors.initials: Z
authors.lastname: Chen
authors.forename: Jane
authors.initials: J
authors.lastname: Lian
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Jitesh
authors.initials: J
authors.lastname: Pratap
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D020868:Gene Silencing; D055413:Growth Differentiation Factor 10 / Q000172:deficiency / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D008780:Methyltransferases; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins; D012886:Skull / Q000166:cytology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C525784:Gdf10 protein, mouse; D055413:Growth Differentiation Factor 10; D012097:Repressor Proteins; C493716:Runx2 protein, mouse; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases