Gene expression profiling after treatment with the histone deacetylase inhibitor trichostatin A reveals altered expression of both pro- and anti-apoptotic genes in pancreatic adenocarcinoma cells

The historic deacetylase inhibitor trichostatin A (TSA) has been previously shown to block cellular growth in G2 and induce apoptosis in human pancreatic cancer cell lines. In order to better understand this phenomenon, we have analyzed the gene expression profiles in PaCa44 cells after treatment with TSA using microarrays containing 22,283 probesets. TSA was found to cause both the induction and repression of a large number of genes, although the number whose expression was up-regulated was greater than the number of genes that were down-regulated. When a threshold value of 3 was used as a cutoff level, a total of 306 (3.4%) of the detectable genes had altered expression. When categorized according to cellular function, the differentially expressed genes were found to be involved in a wide variety of cellular processes, including cell proliferation, signaling, regulation of transcription, and apoptosis. Moreover, Sp1/Sp3 transcription factor binding sites were significantly more abundant among TSA-induced genes. One prominent feature was the increased ratio between the levels of expression of pro-apoptotic (BIM) and anti-apoptotic (Bcl-XL and Bcl-W) genes. This result was confirmed in eight additional pancreatic cancer cell lines after treatment with TSA, suggesting that this event may be a strong determinant for the induction of apoptosis by TSA. (C) 2004 Elsevier B.V. All rights reserved.