title: HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity.
abstract: 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.
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Terek
mesh_terms: D002356:Cartilage / Q000378:metabolism; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009389:Neovascularization, Pathologic; D010641:Phenotype; D012097:Repressor Proteins / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned; C493709:RUNX2 protein, human; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; C400300:HDAC4 protein, human; D006655:Histone Deacetylases