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

Riku Sakimura, Kazuhiro Tanaka, Syunsaku Yamamoto, Tomoya Matsunobu, Xu Li, Masuo Hanada, Takamitsu Okada, Tomoyuki Nakamura, Yang Li, Yukihide Iwamoto

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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 α1 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 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. 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.

Original languageEnglish
Pages (from-to)275-282
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 1 2007

Fingerprint

Chondrosarcoma
Histone Deacetylase Inhibitors
Depsipeptides
Acetylation
Histones
Collagen Type XI
Growth
Collagen Type X
Aggrecans
Collagen Type II
Cell Cycle Checkpoints
Genes
Extracellular Matrix
Research Design
Apoptosis
Phenotype
Drug Therapy
Cell Line
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells. / Sakimura, Riku; Tanaka, Kazuhiro; Yamamoto, Syunsaku; Matsunobu, Tomoya; Li, Xu; Hanada, Masuo; Okada, Takamitsu; Nakamura, Tomoyuki; Li, Yang; Iwamoto, Yukihide.

In: Clinical Cancer Research, Vol. 13, No. 1, 01.01.2007, p. 275-282.

Research output: Contribution to journalArticle

Sakimura, R, Tanaka, K, Yamamoto, S, Matsunobu, T, Li, X, Hanada, M, Okada, T, Nakamura, T, Li, Y & Iwamoto, Y 2007, 'The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells', Clinical Cancer Research, vol. 13, no. 1, pp. 275-282. https://doi.org/10.1158/1078-0432.CCR-06-1696
Sakimura, Riku ; Tanaka, Kazuhiro ; Yamamoto, Syunsaku ; Matsunobu, Tomoya ; Li, Xu ; Hanada, Masuo ; Okada, Takamitsu ; Nakamura, Tomoyuki ; Li, Yang ; Iwamoto, Yukihide. / The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 1. pp. 275-282.
@article{6e14193910d840f797b00973d506e784,
title = "The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells",
abstract = "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 α1 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 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. 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.",
author = "Riku Sakimura and Kazuhiro Tanaka and Syunsaku Yamamoto and Tomoya Matsunobu and Xu Li and Masuo Hanada and Takamitsu Okada and Tomoyuki Nakamura and Yang Li and Yukihide Iwamoto",
year = "2007",
month = "1",
day = "1",
doi = "10.1158/1078-0432.CCR-06-1696",
language = "English",
volume = "13",
pages = "275--282",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells

AU - Sakimura, Riku

AU - Tanaka, Kazuhiro

AU - Yamamoto, Syunsaku

AU - Matsunobu, Tomoya

AU - Li, Xu

AU - Hanada, Masuo

AU - Okada, Takamitsu

AU - Nakamura, Tomoyuki

AU - Li, Yang

AU - Iwamoto, Yukihide

PY - 2007/1/1

Y1 - 2007/1/1

N2 - 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 α1 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 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. 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.

AB - 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 α1 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 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. 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.

UR - http://www.scopus.com/inward/record.url?scp=33846266216&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846266216&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-06-1696

DO - 10.1158/1078-0432.CCR-06-1696

M3 - Article

C2 - 17200366

AN - SCOPUS:33846266216

VL - 13

SP - 275

EP - 282

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -