Cancer Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Oncogene. 2012 Oct 25;31(43):4619-29. doi: 10.1038/onc.2011.612. Epub 2012 Jan 16.
The epithelial-to-mesenchymal transition (EMT) is a crucial program for the invasion and metastasis of epithelial tumors that involves loss of cell-cell adhesion and increased cell mobility; however, mechanisms underlying this transition are not fully elucidated. Here, we propose a novel mechanism through which the nicotinamide adenine dinucleotide-dependent histone deacetylase SIRT1 regulates EMT in prostate cancer cells through cooperation with the EMT inducing transcription factor ZEB1. We found that forced expression of SIRT1 in non-transformed PZ-HPV-7 prostate epithelial cells disrupts the epithelial morphology concomitant with decreased expression of the epithelial marker, E-cadherin, and increased expression of mesenchymal markers. In contrast, silencing SIRT1 in metastatic prostate tumor cells restores cell-cell adhesion and induces a shift toward an epithelial morphology concomitant with increased expression of E-cadherin and decreased expression of mesenchymal markers. We also found that SIRT1 has a physiologically relevant role in endogenous EMT induced by EGF signaling in prostate cancer cells. We propose that the regulation of EMT by SIRT1 involves modulation of, and cooperation with, the EMT inducing transcription factor ZEB1. Specifically, we show that SIRT1 silencing reduces expression of ZEB1 and that SIRT1 is recruited to the E-cadherin proximal promoter by ZEB1 to deacetylate histone H3 and to reduce binding of RNA polymerase II, ultimately suppressing E-cadherin transcription. We thus identify a necessary role for ZEB1 in SIRT1-mediated EMT. Finally, we show that reduction of SIRT1 decreases prostate cancer cell migration in vitro and metastasis in vivo in immunodeficient mice, which is largely independent of any general effects of SIRT1 on prostate cancer growth and survival. We therefore identify SIRT1 as a positive regulator of EMT and metastatic growth of prostate cancer cells and our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse EMT and to prevent prostate cancer progression.
上皮-间充质转化 (EMT) 是上皮肿瘤侵袭和转移的关键程序，涉及细胞-细胞黏附的丧失和细胞迁移能力的增加；然而，这种转化的机制尚未完全阐明。在这里，我们提出了一种新的机制，即烟酰胺腺嘌呤二核苷酸依赖性组蛋白去乙酰化酶 SIRT1 通过与 EMT 诱导转录因子 ZEB1 合作，调节前列腺癌细胞中的 EMT。我们发现，在非转化的 PZ-HPV-7 前列腺上皮细胞中强制表达 SIRT1 会破坏上皮形态，同时降低上皮标志物 E-钙黏蛋白的表达，增加间充质标志物的表达。相比之下，沉默转移性前列腺肿瘤细胞中的 SIRT1 会恢复细胞-细胞黏附，并诱导向上皮形态转变，同时增加 E-钙黏蛋白的表达，降低间充质标志物的表达。我们还发现，SIRT1 在前列腺癌细胞中由 EGF 信号诱导的内源性 EMT 中具有生理相关的作用。我们提出，SIRT1 对 EMT 的调节涉及对 EMT 诱导转录因子 ZEB1 的调节和合作。具体而言，我们表明 SIRT1 沉默会降低 ZEB1 的表达，并且 SIRT1 被 ZEB1 招募到 E-钙黏蛋白近端启动子，以去乙酰化组蛋白 H3 并减少 RNA 聚合酶 II 的结合，最终抑制 E-钙黏蛋白转录。因此，我们确定了 ZEB1 在 SIRT1 介导的 EMT 中的必要作用。最后，我们表明降低 SIRT1 会减少前列腺癌细胞在体外的迁移和在免疫缺陷小鼠体内的转移，这在很大程度上独立于 SIRT1 对前列腺癌细胞生长和存活的任何一般影响。因此，我们确定 SIRT1 是 EMT 和前列腺癌细胞转移生长的正调节剂，我们的发现表明过表达的 SIRT1 可能是逆转 EMT 和预防前列腺癌进展的潜在治疗靶点。
