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

Department of Urology, Experimental Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 06/2011; 10(9):1644-55. DOI: 10.1158/1535-7163.MCT-11-0182
Source: PubMed


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 androgen-dependent 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-κB) 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-κB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies.

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    • "While CBP/p300 has been linked to p21 expression [61,62], we have yet to fully characterize CBP/p300’s involvement in these cells. Furthermore, while CBP/p300 has been reported as a tumor suppressor [63], others report opposite findings [64] as these effects maybe tumor specific. "
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    • "Recently, compound C646 was designed by virtual ligand screening and was shown to be a potent, highly selective, cell permeable small molecule p300 HAT inhibitor [45]. The C646 inhibitor impedes intracellular histone acetylation and slows growth of cancer cells in vitro [45], [46]; however, the effectiveness of C646 in animal and human studies has not been reported. "
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