Inhibitors of histone deacetylases have been approved for clinical application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated and may induce transcription of androgen receptor (AR)-responsive genes, even in the absence or presence of low levels of AR. To discover a potential anticancer effect of p300/CBP inhibition, we used two different approaches: (i) downregulation of p300 and CBP by specific short interfering RNA (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 androgendependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of AR function and decrease of the nuclear factor kappa B (NF-kB) subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP, depletion and was accompanied by lower matrix metalloproteinase (MMP)-2 and MMP-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 AR function and downregulation of p65 impairing several NF-kB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies. Mol Cancer Ther; 10(9); 1644-55. Ó2011 AACR.

p300 and CBP are implicated in regulation of ER-β activity and cellular migration in prostate cancer. These findings are important for understanding of action of ER-β in carcinoma of the prostate.

Supplementary Figure 5 from Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines

Supplementary Figure 3 from 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 not been investigated for their potential use in cancer therapy. In prostate cancer the histone acetyltransferases and coactivators p300 and CBP are upregulated and 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. 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 responsive genes and decrease of expression levels of the NF-κB subunit p65 due to a higher turnover of the protein. Furthermore, cell invasion was decreased upon p300, but not CBP depletion and was accompanied by a lower MMP-9 transcription. 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 the cell permeable small molecule inhibitor of p300/CBP′s acetyltransferase domain. Taken together, those results suggest that p300 inhibition is a promising approach for the development of new anti-cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1622. doi:10.1158/1538-7445.AM2011-1622