Approximately 30% of human lung cancers acquire mutations in eitherKeap1orNfe2l2, resulting in the stabilization of Nrf2, theNfe2l2gene 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.

中文翻译：

---

Nrf2 激活通过抑制 Bach1 的降解促进肺癌转移。

大约 30% 的人类肺癌在 Keap1 或 Nfe2l2 中获得突变，导致 Nrf2 稳定，该 Nrf2 是 Nfe2l2 基因产物，可控制氧化稳态。在这里，我们表明血红素通过促进其与泛素连接酶 Fbxo22 的相互作用来触发 Bach1（一种前转移转录因子）的降解。Nrf2 在肺癌中的积累通过诱导分解代谢血红素的酶 Ho1 来稳定 Bach1。在肺癌小鼠模型中，Keap1 或 Fbxo22 的缺失会以 Bach1 依赖性方式诱导转移。Ho1 的药理学抑制以 Fbxo22 依赖性方式抑制转移。人类转移性肺癌显示出高水平的 Ho1 和 Bach1。Bach1 转录特征与肺癌患者的不良生存和转移有关。