Purpose: Histologically, chondrosarcomas represent the degree of chondrogenic differentiation, which is associated with the prognosis of the disease. Histone acetylation and deacetylation play key roles in the regulation of chondrocytic differentiation. Here, we describe the antitumor effects of histone deacetylase (HDAC) inhibitors as differentiating reagents on chondrosarcomas. Experimental Design: We examined the effects of a HDAC inhibitor, depsipeptide, on the growth of chondrosarcoma cell lines.We also investigated the modulation of the expression levels of extracellular matrix genes and the induction of phenotypic change in chondrosarcoma cells treated with depsipeptide. Finally, we examined the antitumor effect of depsipeptide on chondrosarcoma in vivo. Results: Depsipeptide inhibited the growth of chondrosarcoma cells by inducing cell cycle arrest and/or apoptosis. HDAC inhibitors increased the expression of the a1 chain of type II collagen (COL2A1) gene due to the enhanced histone acetylation in the promoter and enhancer. Depsipeptide also up-regulated the expressions of aggrecan and the a2 chain of type XI collagen (COL11A2) mRNA in a dose-dependent manner. Moreover, long-term treatment with a low dose of depsipeptide resulted in the induction of differentiation into hypertrophic phenotype, as shown by the increment of the a1 chain of type X collagen (COL10A1) expression in chondrosarcoma cells. In vivo studies and histologic analyses confirmed that depsipeptide significantly inhibited tumor growth and induced differentiation into the hypertrophic and mineralized state in chondrosarcoma cells. Conclusions:These results strongly suggest that HDAC inhibitors may be promising reagents for use as a differentiating chemotherapy against chondrosarcomas.Chondrosarcomas represent the second most prevalent primary skeletal malignancy. Because chondrosarcomas are highly resistant to conventional chemotherapy and radiotherapy, surgery is the only effective form of treatment. To date, no effective adjuvant therapy exists for inoperable chondrosarcomas (1, 2). Thus, a novel approach to therapeutic strategy is a priority for improving the prognosis as related to local recurrence, metastasis, and survival.A recent study has shown that the cartilaginous cells of the growth plate during their different states of differentiation and the distinct histologic chondrosarcoma subtypes show striking histologic similarities (3). The normal growth plate represents the chondrocytic maturation process including resting, proliferative, prehypertrophic, and hypertrophic chondrocytes. As a final step, the cartilage matrix becomes mineralized and hypertrophic cells undergo apoptosis. The process is accompanied by the sequential gene expression pattern of the characteristic extracellular matrix. After commitment to the chondrocyte lineage, mesenchymal cells undergo condensation, cease to express type I collagen (COL1), and then differentiate into a chondrocytic phenotype characterized by the expression of type II, IX, and XI...

Supplementary Data Figure 1 from The Effects of Histone Deacetylase Inhibitors on the Induction of Differentiation in Chondrosarcoma Cells

<div>Abstract<p><b>Purpose:</b> Histologically, chondrosarcomas represent the degree of chondrogenic differentiation, which is associated with the prognosis of the disease. Histone acetylation and deacetylation play key roles in the regulation of chondrocytic differentiation. Here, we describe the antitumor effects of histone deacetylase (HDAC) inhibitors as differentiating reagents on chondrosarcomas.</p><p><b>Experimental Design:</b> We examined the effects of a HDAC inhibitor, depsipeptide, on the growth of chondrosarcoma cell lines. We also investigated the modulation of the expression levels of extracellular matrix genes and the induction of phenotypic change in chondrosarcoma cells treated with depsipeptide. Finally, we examined the antitumor effect of depsipeptide on chondrosarcoma <i>in vivo</i>.</p><p><b>Results:</b> Depsipeptide inhibited the growth of chondrosarcoma cells by inducing cell cycle arrest and/or apoptosis. HDAC inhibitors increased the expression of the α1 chain of type II collagen (<i>COL2A1</i>) gene due to the enhanced histone acetylation in the promoter and enhancer. Depsipeptide also up-regulated the expressions of aggrecan and the α2 chain of type XI collagen (COL11A2) mRNA in a dose-dependent manner. Moreover, long-term treatment with a low dose of depsipeptide resulted in the induction of differentiation into hypertrophic phenotype, as shown by the increment of the α1 chain of type X collagen (COL10A1) expression in chondrosarcoma cells. <i>In vivo</i> studies and histologic analyses confirmed that depsipeptide significantly inhibited tumor growth and induced differentiation into the hypertrophic and mineralized state in chondrosarcoma cells.</p><p><b>Conclusions:</b> These results strongly suggest that HDAC inhibitors may be promising reagents for use as a differentiating chemotherapy against chondrosarcomas.</p></div>

<div>Abstract<p><b>Purpose:</b> Histologically, chondrosarcomas represent the degree of chondrogenic differentiation, which is associated with the prognosis of the disease. Histone acetylation and deacetylation play key roles in the regulation of chondrocytic differentiation. Here, we describe the antitumor effects of histone deacetylase (HDAC) inhibitors as differentiating reagents on chondrosarcomas.</p><p><b>Experimental Design:</b> We examined the effects of a HDAC inhibitor, depsipeptide, on the growth of chondrosarcoma cell lines. We also investigated the modulation of the expression levels of extracellular matrix genes and the induction of phenotypic change in chondrosarcoma cells treated with depsipeptide. Finally, we examined the antitumor effect of depsipeptide on chondrosarcoma <i>in vivo</i>.</p><p><b>Results:</b> Depsipeptide inhibited the growth of chondrosarcoma cells by inducing cell cycle arrest and/or apoptosis. HDAC inhibitors increased the expression of the α1 chain of type II collagen (<i>COL2A1</i>) gene due to the enhanced histone acetylation in the promoter and enhancer. Depsipeptide also up-regulated the expressions of aggrecan and the α2 chain of type XI collagen (COL11A2) mRNA in a dose-dependent manner. Moreover, long-term treatment with a low dose of depsipeptide resulted in the induction of differentiation into hypertrophic phenotype, as shown by the increment of the α1 chain of type X collagen (COL10A1) expression in chondrosarcoma cells. <i>In vivo</i> studies and histologic analyses confirmed that depsipeptide significantly inhibited tumor growth and induced differentiation into the hypertrophic and mineralized state in chondrosarcoma cells.</p><p><b>Conclusions:</b> These results strongly suggest that HDAC inhibitors may be promising reagents for use as a differentiating chemotherapy against chondrosarcomas.</p></div>

Supplementary Data Figure 1 from The Effects of Histone Deacetylase Inhibitors on the Induction of Differentiation in Chondrosarcoma Cells