Increased expression of IFI16 protein (encoded by the IFI16 gene) in normal human prostate epithelial cells is associated with cellular senescence-associated cell growth arrest. Consistent with a role for IFI16 protein in cellular senescence, the expression of IFI16 protein is either very low or not detectable in human prostate cancer cell lines. We now report that treatment of DU-145 and LNCaP prostate cancer cell lines with histone deacetylase inhibitor trichostatin A (TSA) or CGK1026 resulted in transcriptional activation of the IFI16 gene. The induction of IFI16 protein in LNCaP cells was dependent on the duration of TSA treatment. Furthermore, TSA treatment of LNCaP cells up-regulated the expression of Janus-activated kinase 1 protein kinase and modulated the transcription of certain IFN-activatable genes. However, overexpression of exogenous Janus-activated kinase 1 protein in LNCaP cells and treatment of cells with IFNs (alpha and gamma) did not increase the expression of IFI16. Instead, the transcriptional activation of IFI16 gene by TSA treatment of LNCaP cells was dependent on transcriptional activation by c-Jun/activator protein-1 transcription factor. Importantly, increased expression of IFI16 in LNCaP cells was associated with decreases in the expression of androgen receptor and apoptosis of cells. Conversely, knockdown of IFI16 expression in TSA-treated LNCaP cells increased androgen receptor protein levels with concomitant decreases in apoptosis. Together, our observations provide support for the idea that histone deacetylase-dependent transcriptional silencing of the IFI16 gene in prostate epithelial cells contributes to the development of prostate cancer.