Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines

Inhibitors of histone deacetylases have been approved for clinical application in cancer treatment. On the other hand, histone acetyltransferase inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer the histone acetyltransferases and coactivators p300 and CBP are upregulated and may induce transcription of androgen-receptor responsive genes, even in the absence or in the presence of low levels of androgen receptor. To discover a potential anti-cancer effect of p300/CBP inhibition, we used two different approaches: i) downregulation of p300 and CBP by specific siRNA and ii) chemical inhibition of the acetyltransferase activity by a newly developed small molecule, C646. Knockdown of p300 by specific siRNA, but surprisingly not of CBP, led to an increase of caspase-dependent apoptosis involving both extrinsic and intrinsic cell death pathways in androgen-dependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of androgen receptor function and decrease of the NF-κB subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP depletion and was accompanied by lower MMP-2 and -9 transcriptions. Thus, p300 and CBP have differential roles in the processes of survival and invasion of prostate cancer cells. Induction of apoptosis in prostate cancer cells was confirmed by the use of C646. This was substantiated by a decrease of androgen receptor function and downregulation of p65 impairing several NF-κB target genes. Taken together, those results suggest that p300 inhibition may be a promising approach for the development of new anti-cancer therapies.