This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pratap, J. Articles by Lian, J. B. Search for Related Content PubMed PubMed Citation Articles by Pratap, J. Articles by Lian, J. B.

The Runx2 Osteogenic Transcription Factor Regulates Matrix Metalloproteinase 9 in Bone Metastatic Cancer Cells and Controls Cell Invasion

Departments of Cell Biology,¹ Cancer Biology,² Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655³

Received 7 January 2005/ Returned for modification 8 February 2005/ Accepted 20 June 2005

The Runx2 (Cbfa1/AML3) transcription factor and matrix metalloproteinase 9 (MMP9) are key regulators of growth plate maturation and bone formation. The genes for both proteins are characteristic markers of breast and prostate cancer cells that metastasize to bone. Here we experimentally addressed the compelling question of whether Runx2 and MMP are functionally linked. By cDNA expression array analysis, we identified MMP9 as a novel downstream target of Runx2. Like that of MMP13, MMP9 expression is nearly depleted in Runx2 mutant mice. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the recruitment of Runx2 to the MMP9 promoter. We show by mutational analysis that the Runx2 site mediates transactivation of the MMP9 promoter in osteoblasts (MC3T3-E1) and nonosseous (HeLa) cells. The overexpression of Runx2 by adenovirus delivery in nonmetastatic (MCF-7) and metastatic breast (MDA-MB-231) and prostate (PC3) cancer cell lines significantly increases the endogenous levels of MMP9. The knockdown of Runx2 by RNA interference decreases MMP9 expression, as well as that of other Runx2 target genes, including the genes for MMP13 and vascular endothelial growth factor. Importantly, we have demonstrated using a cell invasion assay that Runx2-regulated MMP9 levels are functionally related to the invasion properties of cancer cells. These results are consistent with Runx2 control of multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.

This article has been cited by other articles:

• Ali, S. A., Zaidi, S. K., Dacwag, C. S., Salma, N., Young, D. W., Shakoori, A. R., Montecino, M. A., Lian, J. B., van Wijnen, A. J., Imbalzano, A. N., Stein, G. S., Stein, J. L. (2008). Phenotypic transcription factors epigenetically mediate cell growth control. Proc. Natl. Acad. Sci. USA 105: 6632-6637 [Abstract] [Full Text]  
• Fowlkes, J. L., Bunn, R. C., Liu, L., Wahl, E. C., Coleman, H. N., Cockrell, G. E., Perrien, D. S., Lumpkin, C. K. Jr., Thrailkill, K. M. (2008). Runt-Related Transcription Factor 2 (RUNX2) and RUNX2-Related Osteogenic Genes Are Down-Regulated throughout Osteogenesis in Type 1 Diabetes Mellitus. Endocrinology 149: 1697-1704 [Abstract] [Full Text]  
• Chang, S.-F., Chang, C. A., Lee, D.-Y., Lee, P.-L., Yeh, Y.-M., Yeh, C.-R., Cheng, C.-K., Chien, S., Chiu, J.-J. (2008). Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad. Proc. Natl. Acad. Sci. USA 105: 3927-3932 [Abstract] [Full Text]  
• Lamour, V., Detry, C., Sanchez, C., Henrotin, Y., Castronovo, V., Bellahcene, A. (2007). Runx2- and Histone Deacetylase 3-mediated Repression Is Relieved in Differentiating Human Osteoblast Cells to Allow High Bone Sialoprotein Expression. J. Biol. Chem. 282: 36240-36249 [Abstract] [Full Text]  
• Zaidi, S. K., Pande, S., Pratap, J., Gaur, T., Grigoriu, S., Ali, S. A., Stein, J. L., Lian, J. B., van Wijnen, A. J., Stein, G. S. (2007). Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential. Proc. Natl. Acad. Sci. USA 104: 19861-19866 [Abstract] [Full Text]  
• Kingsley, L. A., Fournier, P. G.J., Chirgwin, J. M., Guise, T. A. (2007). Molecular Biology of Bone Metastasis. Molecular Cancer Therapeutics 6: 2609-2617 [Abstract] [Full Text]  
• Lien, C.-Y., Lee, O. K., Su, Y. (2007). Cbfb Enhances the Osteogenic Differentiation of Both Human and Mouse Mesenchymal Stem Cells Induced by Cbfa-1 via Reducing Its Ubiquitination-Mediated Degradation. Stem Cells 25: 1462-1468 [Abstract] [Full Text]  
• Chirgwin, J. M., Guise, T. A. (2006). Does Prostate-Specific Antigen Contribute to Bone Metastases?. Clin. Cancer Res. 12: 1395-1397 [Full Text]