Abstract
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. 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. Depsipeptide inhibited the growth of chondrosarcoma cells by inducing cell cycle arrest and/or apoptosis. HDAC inhibitors increased the expression of the alpha1 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 alpha2 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 alpha1 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. These results strongly suggest that HDAC inhibitors may be promising reagents for use as a differentiating chemotherapy against chondrosarcomas.
Highlights
Chondrosarcomas represent the degree of chondrogenic differentiation, which is associated with the prognosis of the disease
A report has shown that treatment with the histone deacetylase (HDAC) inhibitor trichostatin A enhances the expression of the a1 chain of type II collagen (COL2A1) and aggrecan in human primary chondrocytes [10]
Depsipeptide inhibits the growth of chondrosarcoma cells by inducing cell cycle arrest and apoptosis
Summary
Chondrosarcomas represent the degree of chondrogenic differentiation, which is associated with the prognosis of the disease. 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. Histochemical and immunohistochemical analyses have shown that chondrosarcomas showing mainly mature and terminally differentiated (hypertrophic) chondrocytic phenotypes display only scant proliferation, whereas less differentiated chondrosarcomas with the phenotype of dedifferentiated chondrocytes show significantly higher proliferative activity [4] These features are highly correlated with prognosis [5]. A report has shown that treatment with the histone deacetylase (HDAC) inhibitor trichostatin A enhances the expression of the a1 chain of type II collagen (COL2A1) and aggrecan in human primary chondrocytes [10]. This is the first report showing the potential clinical usefulness of HDAC inhibitors in the treatment of chondrosarcomas
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