Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1
Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1
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DOI：
10.1016/j.cell.2019.06.003
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发表时间：
2019-07-11
期刊：
影响因子：
64.5
通讯作者：
Pagano, Michele
中科院分区：
文献类型：
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作者：
Lignitto, Luca;LeBoeuf, Sarah E.;Pagano, Michele
大约30%的人类肺癌获得Keap1或Nfe2l2突变，导致控制氧化稳态的Nfe2l2基因产物Nrf2稳定。在这里，我们发现血红素通过促进其与泛素连接酶Fbxo22的相互作用，触发了促转移转录因子Bach1的降解。Nrf2在肺癌中的积累通过诱导Ho1（分解血红素的酶）导致Bach1的稳定。在肺癌小鼠模型中，Keap1或Fbxo22的缺失以bach1依赖的方式诱导转移。药理抑制Ho1以依赖fbxo22的方式抑制转移。人类转移性肺癌显示高水平的Ho1和Bach1。Bach1转录特征与肺癌患者生存不良和转移有关。我们提出Nrf2通过抑制血红素和fbxo22介导的Bach1降解来激活转移程序，并且Ho1抑制剂代表了预防肺癌转移的有效治疗策略。
Approximately 30% of human lung cancers acquire mutations in either Keap1 or Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which controls oxidative homeostasis. Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival and metastasis in lung cancer patients. We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.