Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4675-80. doi: 10.1073/pnas.0907705107. Epub 2010 Feb 22.
The HIF family of hypoxia-inducible transcription factors are key mediators of the physiologic response to hypoxia, whose dysregulation promotes tumorigenesis. One important HIF-1 effector is the REDD1 protein, which is induced by HIF-1 and which functions as an essential regulator of TOR complex 1 (TORC1) activity in Drosophila and mammalian cells. Here we demonstrate a negative feedback loop for regulation of HIF-1 by REDD1, which plays a key role in tumor suppression. Genetic loss of REDD1 dramatically increases HIF-1 levels and HIF-regulated target gene expression in vitro and confers tumorigenicity in vivo. Increased HIF-1 in REDD1(-/-) cells induces a shift to glycolytic metabolism and provides a growth advantage under hypoxic conditions, and HIF-1 knockdown abrogates this advantage and suppresses tumorigenesis. Surprisingly, however, HIF-1 up-regulation in REDD1(-/-) cells is largely independent of mTORC1 activity. Instead, loss of REDD1 induces HIF-1 stabilization and tumorigenesis through a reactive oxygen species (ROS) -dependent mechanism. REDD1(-/-) cells demonstrate a substantial elevation of mitochondrial ROS, and antioxidant treatment is sufficient to normalize HIF-1 levels and inhibit REDD1-dependent tumor formation. REDD1 likely functions as a direct regulator of mitochondrial metabolism, as endogenous REDD1 localizes to the mitochondria, and this localization is required for REDD1 to reduce ROS production. Finally, human primary breast cancers that have silenced REDD1 exhibit evidence of HIF activation. Together, these findings uncover a specific genetic mechanism for HIF induction through loss of REDD1. Furthermore, they define REDD1 as a key metabolic regulator that suppresses tumorigenesis through distinct effects on mTORC1 activity and mitochondrial function.
缺氧诱导因子（HIF）家族是缺氧生理反应的关键介质，其失调会促进肿瘤发生。HIF-1 的一个重要效应物是 REDD1 蛋白，它受 HIF-1 诱导，在果蝇和哺乳动物细胞中作为 TOR 复合物 1（TORC1）活性的必需调节剂发挥作用。在这里，我们证明了 REDD1 对 HIF-1 的负反馈调节环路，它在肿瘤抑制中起着关键作用。遗传缺失 REDD1 会显著增加体外 HIF-1 水平和 HIF 调节的靶基因表达，并赋予体内致瘤性。REDD1(-/-)细胞中增加的 HIF-1 诱导糖酵解代谢的转变，并在低氧条件下提供生长优势，而 HIF-1 敲低则消除了这种优势并抑制了肿瘤发生。然而，令人惊讶的是，REDD1(-/-)细胞中 HIF-1 的上调在很大程度上独立于 mTORC1 活性。相反，REDD1 的缺失通过活性氧（ROS）依赖性机制诱导 HIF-1 稳定和肿瘤发生。REDD1(-/-)细胞表现出大量的线粒体 ROS 升高，抗氧化剂处理足以使 HIF-1 水平正常化并抑制 REDD1 依赖性肿瘤形成。REDD1 可能作为线粒体代谢的直接调节剂发挥作用，因为内源性 REDD1 定位于线粒体，并且这种定位对于 REDD1 减少 ROS 产生是必需的。最后，沉默 REDD1 的人类原发性乳腺癌表现出 HIF 激活的证据。总之，这些发现揭示了通过 REDD1 缺失诱导 HIF 的特定遗传机制。此外，它们将 REDD1 定义为一种关键的代谢调节剂，通过对 mTORC1 活性和线粒体功能的不同影响来抑制肿瘤发生。
