Department of Urology, Experimental Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Mol Cancer Ther. 2011 Sep;10(9):1644-55. doi: 10.1158/1535-7163.MCT-11-0182. Epub 2011 Jun 27.
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.
组蛋白去乙酰化酶抑制剂已被批准用于癌症治疗的临床应用。另一方面，组蛋白乙酰转移酶 (HAT) 抑制剂在癌症治疗中的潜在用途研究较少。在前列腺癌中，HATs 和共激活因子 p300 和 CBP 上调，即使在 AR 水平低或不存在的情况下，也可能诱导雄激素受体 (AR) 反应基因的转录。为了发现 p300/CBP 抑制的潜在抗癌作用，我们使用了两种不同的方法：（i）使用特异性短发夹 RNA (siRNA) 下调 p300 和 CBP，和（ii）使用新开发的小分子 C646 抑制乙酰转移酶活性。特异性 siRNA 下调 p300，但令人惊讶的是 CBP 没有，导致依赖雄激素和去势抵抗的前列腺癌细胞中 caspase 依赖性凋亡增加，涉及外在和内在细胞死亡途径。凋亡的诱导是通过几种途径介导的，包括抑制 AR 功能和降低核因子 kappa B (NF-κB) 亚单位 p65。此外，p300 耗尽会降低细胞侵袭，而 CBP 耗尽则不会，并且伴随着基质金属蛋白酶 (MMP)-2 和 MMP-9 转录的降低。因此，p300 和 CBP 在前列腺癌细胞的存活和侵袭过程中具有不同的作用。C646 的使用证实了前列腺癌细胞中的凋亡诱导。这是通过降低 AR 功能和下调 p65 证实的，p65 下调会损害几个 NF-κB 靶基因。总之，这些结果表明，p300 抑制可能是开发新抗癌疗法的有前途的方法。
