Department of Urology and Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Int J Cancer. 2010 Apr 1;126(7):1538-48. doi: 10.1002/ijc.24928.
Dietary compounds and epigenetic influences are well recognized factors in cancer progression. Resveratrol (Res), a dietary compound from grapes, has anticancer properties; however, its epigenetic effects are understudied. Metastasis-associated protein 1 (MTA1) is a part of the nucleosome remodeling deacetylation (NuRD) corepressor complex that mediates posttranslational modifications of histones and nonhistone proteins resulting in transcriptional repression. MTA1 overexpression in prostate cancer (PCa) correlates with tumor aggressiveness and metastasis. In this study, we have identified a novel MTA1-mediated mechanism, by which Res restores p53-signaling pathways in PCa cells. We show, for the first time, that Res causes down-regulation of MTA1 protein, leading to destabilization of MTA1/NuRD thus allowing acetylation/activation of p53. We demonstrated that MTA1 decrease by Res was concomitant with accumulation of Ac-p53. MTA1 knockdown further sensitized PCa cells to Res-dependent p53 acetylation and recruitment to the p21 and Bax promoters. Furthermore, MTA1 silencing maximized the levels of Res-induced apoptosis and pro-apoptotic Bax accumulation. HDAC inhibitor SAHA, like MTA1 silencing, increased Res-dependent p53 acetylation and showed cooperative effect on apoptosis. Our results indicate a novel epigenetic mechanism that contributes to Res anticancer activities: the inhibition of MTA1/NuRD complexes due to MTA1 decrease, which suppresses its deacetylation function and allows p53 acetylation and subsequent activation of pro-apoptotic genes. Our study identifies MTA1 as a new molecular target of Res that may have important clinical applications for PCa chemoprevention and therapy, and points to the combination of Res with HDAC inhibitors as an innovative therapeutic strategy for the treatment of PCa.
膳食化合物和表观遗传影响是癌症进展中公认的因素。白藜芦醇（Res）是一种来自葡萄的膳食化合物，具有抗癌特性；然而，其表观遗传作用仍在研究中。转移相关蛋白 1（MTA1）是核小体重塑去乙酰化（NuRD）核心抑制复合物的一部分，介导组蛋白和非组蛋白蛋白质的翻译后修饰，导致转录抑制。前列腺癌（PCa）中 MTA1 的过表达与肿瘤侵袭性和转移相关。在这项研究中，我们确定了一种新的 MTA1 介导的机制，通过该机制 Res 在 PCa 细胞中恢复了 p53 信号通路。我们首次表明，Res 导致 MTA1 蛋白下调，导致 MTA1/NuRD 不稳定，从而允许 p53 乙酰化/激活。我们证明 Res 引起的 MTA1 减少伴随着 Ac-p53 的积累。Res 依赖性 p53 乙酰化和募集到 p21 和 Bax 启动子，MTA1 敲低进一步使 PCa 细胞敏感。此外，MTA1 沉默最大限度地提高了 Res 诱导的细胞凋亡和促凋亡 Bax 积累的水平。与 MTA1 沉默一样，HDAC 抑制剂 SAHA 增加了 Res 依赖性 p53 乙酰化，并显示出对细胞凋亡的协同作用。我们的研究结果表明了一种新的表观遗传机制，有助于 Res 的抗癌活性：由于 MTA1 减少导致 MTA1/NuRD 复合物的抑制，从而抑制其去乙酰化功能，并允许 p53 乙酰化和随后激活促凋亡基因。我们的研究将 MTA1 鉴定为 Res 的一个新的分子靶标，这可能对 PCa 的化学预防和治疗具有重要的临床应用，并指出 Res 与 HDAC 抑制剂的联合使用是治疗 PCa 的一种创新治疗策略。
