HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity

Chondrosarcoma is a primary bone tumor with a dismal prognosis; most patients with this disease develop fatal pulmonary metastases, suggesting the need for a better systemic treatment. Anti-angiogenesis treatment may be useful, because angiogenesis is critical for both tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic factor and is regulated by pathways related to the normal physiologic response to hypoxia and genetic alterations related to the malignant phenotype. Our prior work has shown that VEGF is overexpressed in high grade chondrosarcoma and chondrosarcoma cell lines. Working on the premise that developmental pathways giving a selective growth advantage are often recapitulated in tumors, we investigated the regulation of VEGF by HDAC4 and Runx2 in chondrosarcoma. We tested the hypothesis that there is dysregulation of HDAC4/Runx2/VEGF gene expression and that decreased HDAC4 expression accounts for at least some of the increased VEGF expression seen in chondrosarcoma. We show that reduced expression of HDAC4 in chondrosarcoma cells increases expression of Runx2 leading to increased expression of VEGF and in vitro angiogenesis. Thus, both hypoxia and dysregulated expression of a developmental pathway are causes of increased VEGF expression in chondrosarcoma.