Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells

被引:131
作者
Hrzenjak, Andelko
Moinfar, Farid
Kremser, Marie-Luise
Strohmeier, Bettina
Staber, Philipp B.
Zatloukal, Kurt
Denk, Helmut
机构
[1] Med Univ Graz, Dept Pathol, A-8036 Graz, Austria
[2] Med Univ Graz, Div Hematol, A-8036 Graz, Austria
关键词
D O I
10.1158/1535-7163.MCT-05-0480
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Covalent modifications of histone proteins, in particular deacetylation of lysine residues, are important for the regulation of gene transcription both in normal and malignant cells. These processes are controlled by histone acetyltransferases and histone deacetylases (HDAC) and have up to now not been described in solid mesenchymal tumors. The present study shows differences in the HDAC1 and HDAC2 expression in endometrial stromal sarcomas (ESS) and a cognate cell line (ESS-1) compared with nonneoplastic endometrial stroma. We show for the first time that HDAC2 expression is consistently increased in ESS. In contrast, HDAC1 expression is generally lower than HDAC2 both in nonneoplastic stroma and in ESS, suggesting that these two proteins, although closely related, are regulated in different ways. In vitro experiments with an ESS cell line showed that valproate, an inhibitor of the class 1 HDACs, led to significant HDAC2 decrease and to cell differentiation. HDAC2 inhibition in ESS-1 cells caused significant changes in the cell cycle by inhibiting G(1)-S transition and influencing expression of p21(WAF1) and cyclin D1. Moreover, in ESS-1 cells, increased expression of the p21(WAF1) was associated with reduction of HDAC2 expression after transfection with small interfering RNA directed against HDAC2. Our results suggest that HDAC2 might be considered as potential drug target in the therapy of ESS and that HDAC inhibitors should be further evaluated in clinical trials in ESS.
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收藏
页码:2203 / 2210
页数:8
相关论文
共 39 条
  • [1] Annunziato AT, 2000, GENE EXPRESSION, V9, P37
  • [2] Cress WD, 2000, J CELL PHYSIOL, V184, P1, DOI 10.1002/(SICI)1097-4652(200007)184:1<1::AID-JCP1>3.0.CO
  • [3] 2-7
  • [4] Histone deacetylases (HDACs): characterization of the classical HDAC family
    De Ruijter, AJM
    Van Gennip, AH
    Caron, HN
    Kemp, S
    Van Kuilenburg, ABP
    [J]. BIOCHEMICAL JOURNAL, 2003, 370 : 737 - 749
  • [5] ELDEIRY WS, 1995, CANCER RES, V55, P2910
  • [6] Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells
    Göttlicher, M
    Minucci, S
    Zhu, P
    Krämer, OH
    Schimpf, A
    Giavara, S
    Sleeman, JP
    Lo Coco, F
    Nervi, C
    Pelicci, PG
    Heinzel, T
    [J]. EMBO JOURNAL, 2001, 20 (24) : 6969 - 6978
  • [7] The human histone deacetylase family
    Gray, SG
    Ekström, TJ
    [J]. EXPERIMENTAL CELL RESEARCH, 2001, 262 (02) : 75 - 83
  • [8] Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia
    Grignani, F
    De Matteis, S
    Nervi, C
    Tomassoni, L
    Gelmetti, V
    Cioce, M
    Fanelli, M
    Ruthardt, M
    Ferrara, FF
    Zamir, I
    Seiser, C
    Grignani, F
    Lazar, MA
    Minucci, S
    Pelicci, PG
    [J]. NATURE, 1998, 391 (6669) : 815 - 818
  • [9] Cholinergic stimulation of early growth response-1 DNA binding activity requires protein kinase C and mitogen-activated protein kinase kinase activation and is inhibited by sodium valproate in SH-SY5Y cells
    Grimes, CA
    Jope, RS
    [J]. JOURNAL OF NEUROCHEMISTRY, 1999, 73 (04) : 1384 - 1392
  • [10] Histone acetylation in chromatin structure and transcription
    Grunstein, M
    [J]. NATURE, 1997, 389 (6649) : 349 - 352