被撤回的出版物: Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2 (Retracted article. See vol. 295, pg. 294, 2020)

Cyclooxygenase- 2 ( COX- 2) is considered to be a target for anticancer therapy. Histone deacetylase ( HDAC) inhibitors exhibit antitumor activity, but the mechanisms of action are incompletely understood. We investigated whether HDAC inhibitors blocked AP- 1- mediated activation of COX- 2 transcription. Trichostatin A and suberoylanilide hydroxamic acid, two structurally related inhibitors of HDAC activity, blocked AP- 1- mediated induction of COX- 2 expression and prostaglandin E2 biosynthesis. Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c- Jun binding to the COX- 2 promoter and thereby blocked transcription. The observed reduction in binding reflected reduced levels of c- Jun. HDAC inhibitors suppressed the induction of c- jun transcription by blocking the recruitment of the preinitiation complex ( RNA polymerase II and TFIIB) to the c- jun promoter. HDAC3 but not HDAC1 or HDAC2 was required for AP- 1- mediated stimulation of c- jun expression. Because HDAC inhibitors suppressed the induction of c- jun gene expression, resulting in reduced COX- 2 transcription, it was important to determine whether other known AP- 1 target genes were also modulated. Cyclin D1 and collagenase- 1 are AP- 1- dependent genes that have been implicated in carcinogenesis. HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase- 1 transcription by inhibiting the binding of c- Jun to the respective promoters. Taken together, these results suggest that HDAC inhibitors block the induction of c- jun transcription by inhibiting the recruitment of the preinitiation complex to the c- jun promoter. This led, in turn, to reduced expression of several activator protein- 1- dependent genes ( COX- 2, cyclin D1, collagenase- 1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors.