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01-05-2012 | Laboratory Investigation

P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells

Authors: K. Bajbouj, C. Mawrin, R. Hartig, J. Schulze-Luehrmann, A. Wilisch-Neumann, A. Roessner, R. Schneider-Stock

Published in: Journal of Neuro-Oncology | Issue 3/2012

Abstract

Glioblastomas are known to be highly chemoresistant, but HDAC inhibitors (HDACi) have been shown to be of therapeutic relevance for this aggressive tumor type. We treated U87 glioblastoma cells with trichostatin A (TSA) to define potential epigenetic targets for HDACi-mediated antitumor effects. Using a cDNA array analysis covering 96 cell cycle genes, cyclin-dependent kinase inhibitor p21^WAF1 was identified as the major player in TSA-induced cell cycle arrest. TSA slightly inhibited proliferation and viability of U87 cells, cumulating in a G1/S cell cycle arrest. This effect was accompanied by a significant up-regulation of p53 and its transcriptional target p21^WAF1 and by down-regulation of key G1/S regulators, such as cdk4, cdk6, and cyclin D1. Nevertheless, TSA did not induce apoptosis in U87 cells. As expected, TSA promoted the accumulation of total acetylated histones H3 and H4 and a decrease in endogenous HDAC activity. Characterizing the chromatin modulation around the p21^WAF1 promoter after TSA treatment using chromatin immunoprecipitation, we found (1) a release of HDAC1, (2) an increase of acetylated H4 binding, and (3) enhanced recruitment of p53. p53-depleted U87 cells showed an abrogation of the G1/S arrest and re-entered the cell cycle. Immunofluorescence staining revealed that TSA induced the nuclear translocation of p21^WAF1 verifying a cell cycle arrest. On the other hand, a significant portion of p21^WAF1 was present in the cytoplasmic compartment causing apoptosis resistance. Furthermore, TSA-treated p53-mutant cell line U138 failed to show an induction in p21^WAF1, showed a deficient G2/M checkpoint, and underwent mitotic catastrophe. We suggest that HDAC inhibition in combination with other clinically used drugs may be considered an effective strategy to overcome chemoresistance in glioblastoma cells.

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Title: P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells
Authors: K. Bajbouj
C. Mawrin
R. Hartig
J. Schulze-Luehrmann
A. Wilisch-Neumann
A. Roessner
R. Schneider-Stock
Publication date: 01-05-2012
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 3/2012
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-011-0791-2

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P53-dependent antiproliferative and pro-apoptotic effects of trichostatin A (TSA) in glioblastoma cells

Abstract

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Abstract

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