The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells.
OBJECTIVE
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.


METHODS
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 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.


CONCLUSIONS
These results strongly suggest that HDAC inhibitors may be promising reagents for use as a differentiating chemotherapy against chondrosarcomas.
Sakimura
Riku
R
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka City, Japan.
Tanaka
Kazuhiro
K
Yamamoto
Syunsaku
S
Matsunobu
Tomoya
T
Li
Xu
X
Hanada
Masuo
M
Okada
Takamitsu
T
Nakamura
Tomoyuki
T
Li
Yang
Y
Iwamoto
Yukihide
Y
D017209:Apoptosis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D002813:Chondrosarcoma / Q000188:drug therapy*; D047630:Depsipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007150:Immunohistochemistry; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation
D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger