Abstract
BackgroundThe 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.ResultsHere 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.ConclusionsOur 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.
Highlights
The Runt-related transcription factor Runx2 is essential for bone development but is implicated in progression of several cancers of breast, prostate and bone, where it activates cancer-related genes and promotes invasive properties
Our results show a dose-dependent repression of Bone morphogenetic protein-3B (BMP-3B) mRNA levels by Runx2 in primary osteoblastic cells
These results suggested that BMP-3B is a novel Runx2 responsive gene
Summary
The Runt-related transcription factor Runx is essential for bone development but is implicated in progression of several cancers of breast, prostate and bone, where it activates cancer-related genes and promotes invasive properties. The chromatin structure is altered by acetylation, phosphorylation and methylation of histone tails [2]. Runx transcription factors (Runx, Runx and Runx3) are critical regulators of organogenesis and cell differentiation regulatory pathways, and mutations in these genes are associated with several cancers. Runx activates cancer-related genes, promotes cells invasive properties [6,8,9,10], cooperates with oncogenes (e.g., c-myc in T-cell lymphoma development), and suppresses apoptotic and growth arrest pathways [11,12]. Runx is a major target gene of TGFβ /BMP signaling pathway and the interaction between Runx and Smads results in regulation of downstream target genes in osteoblasts [13], chondrocytes [14] and cancer cells [8]
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