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Research Articles: Therapeutics

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

¹ Department of Pathology and ² Division of Hematology, Medical University of Graz, Graz, Austria

Requests for reprints: Andelko Hrzenjak, Department of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria. Phone: 43-316-380-76-41; Fax: 43-316-384-329. E-mail: andelko.hrzenjak{at}klinikum-graz.at

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 I 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 G₁-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. [Mol Cancer Ther 2006;5(9):2203–10]

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³ http://www.amc.uva.nl.

Received 11/21/05; revised 6/ 8/06; accepted 6/29/06.