Feedback loop between p66Shc and Nrf2 promotes lung cancer progression
Feedback loop between p66Shc and Nrf2 promotes lung cancer progression
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p66Shc 和 Nrf2 之间的反馈环促进肺癌进展
DOI：
10.1016/j.canlet.2013.05.016
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发表时间：
2013-08-28
期刊：
影响因子：
9.7
通讯作者：
Liu, Zhe
中科院分区：
文献类型：
--
作者：
Du, Wei;Jiang, Yuan;Liu, Zhe
p66（Shc）是SHC1基因编码的蛋白质之一，促进细胞死亡并报告细胞锚定状态，在体外介导失巢凋亡，在体内作为转移抑制剂起作用。然而，对癌细胞中的p66（Shc）基因调控知之甚少。在这里，我们表明，在早期转录后区域的特定CpG位点的甲基化与p66（Shc）抑制在临床人类肺癌样本和癌细胞系。我们还发现应激相关转录因子Nrf2与p66（Shc）基因启动子的甲基化区域相结合，促进p66（Shc）基因的转录。然而，通过Nrf2诱导p66（Shc）需要p66（Shc）启动子中Nrf2结合位点的去甲基化。p66（Shc）的敲低导致Nrf2表达的正反馈上调，因此，发现Nrf2在具有低p66（Shc）表达的肿瘤中高度表达。此外，Nrf2表达水平与患者的肿瘤分级正相关。因此，我们提出，癌细胞中p66（Shc）的表观遗传抑制可能是导致Nrf2上调，增加细胞存活和肿瘤进展的关键因素。(C)2013爱思唯尔爱尔兰有限公司版权所有。
p66(Shc), one of the SHC1 gene encoding proteins, promotes cell death and reports cell anchorage status, mediating anoikis in vitro and functioning as a metastasis suppressor in vivo. However, very little is known about p66(Shc) gene regulation in cancer cells. Here, we show that methylation of a specific CpG site in the early post-transcriptional region correlates with p66(Shc) repression in clinical human lung cancer samples and cancer cell lines. We also find that the stress related transcription factor Nrf2 associates with p66(Shc) gene promoter in the methylated region, and promotes p66(Shc) transcription. However, p66(Shc) induction by Nrf2 requires demethylation of the Nrf2 binding site in p66(Shc) promoter. Knock-down of p66(Shc) leads to a positive feedback upregulation of Nrf2 expression and accordingly, Nrf2 is found to be highly expressed in tumors with low p66(Shc) expression. Further, Nrf2 expression level positively correlates with tumor grade of patients. Thus, we propose that epigenetic repression of p66(Shc) in cancer cells might be a key factor leading to Nrf2 upregulation, increased cell survival, and tumor progression. (C) 2013 Elsevier Ireland Ltd. All rights reserved.