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Negative Feedback Control of HIF-1 Through REDD1-Regulated ROS Suppresses Tumorigenesis

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Negative Feedback Control of HIF-1 Through REDD1-Regulated ROS Suppresses Tumorigenesis Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis Peter Horaka,1, Andrew R. Crawforda,1, Douangsone D. Vadysirisacka, Zachary M. Nasha, M. Phillip DeYounga, Dennis Sgroib, and Leif W. Ellisena,2 aMassachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114; and bDepartment of Pathology, Massachusetts General Hospital, Boston, MA 02114 Edited by Gregg L. Semenza, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 27, 2010 (received for review July 23, 2009) The HIF family of hypoxia-inducible transcription factors are key An additional mechanism for HIF regulation is through reactive mediators of the physiologic response to hypoxia, whose dysre- oxygen species (ROS). Hypoxia is known to induce a burst of gulation promotes tumorigenesis. One important HIF-1 effector is mitochondrial ROS which has been demonstrated by multiple the REDD1 protein, which is induced by HIF-1 and which functions groups to contribute to HIFα stabilization under hypoxic con- as an essential regulator of TOR complex 1 (TORC1) activity in ditions (8–10). The precise mechanisms of this effect are being Drosophila and mammalian cells. Here we demonstrate a negative intensively investigated (11). A specific role for ROS in promoting feedback loop for regulation of HIF-1 by REDD1, which plays a key HIFα stabilization in cancer is suggested by work demonstrating role in tumor suppression. Genetic loss of REDD1 dramatically that the ability of antioxidants to suppress tumorigenesis in some increases HIF-1 levels and HIF-regulated target gene expression model systems is mediated through their ability to inhibit HIF (12). in vitro and confers tumorigenicity in vivo. Increased HIF-1 in As noted above, HIF itself has been shown to suppress oxidative −/− REDD1 cells induces a shift to glycolytic metabolism and pro- phosphorylation and ROS production (3, 4), suggesting the pos- vides a growth advantage under hypoxic conditions, and HIF-1 sibility of a negative feedback loop for HIF regulation by ROS. knockdown abrogates this advantage and suppresses tumorigen- Nevertheless, a specific genetic mechanism for such a ROS-HIF −/− esis. Surprisingly, however, HIF-1 up-regulation in REDD1 cells is pathway in human cancer has not been demonstrated. largely independent of mTORC1 activity. Instead, loss of REDD1 REDD1 (also known as RTP801, DDIT4, and Dig1) was ini- induces HIF-1 stabilization and tumorigenesis through a reactive tially identified as a hypoxia-regulated HIF-1 target gene involved MEDICAL SCIENCES −/− oxygen species (ROS) -dependent mechanism. REDD1 cells dem- in regulation of cell survival (13). Subsequent genetic studies onstrate a substantial elevation of mitochondrial ROS, and antiox- demonstrated a major function of REDD1 and its orthologs as a idant treatment is sufficient to normalize HIF-1 levels and inhibit hypoxia-induced regulator of TORC1 activity both in Drosophila −/− REDD1-dependent tumor formation. REDD1 likely functions as a and mammalian cells (14, 15). Thus, in REDD1 cells, mTORC1 direct regulator of mitochondrial metabolism, as endogenous activity is not appropriately suppressed in response to hypoxia REDD1 localizes to the mitochondria, and this localization is (14, 16). The mechanism of this effect involves the ability of required for REDD1 to reduce ROS production. Finally, human pri- hypoxia-induced REDD1 to activate the tuberous sclerosis tumor mary breast cancers that have silenced REDD1 exhibit evidence of suppressor complex TSC1/2, an upstream inhibitor of mTORC1, HIF activation. Together, these findings uncover a specific genetic by titrating away inhibitory 14-3-3 proteins from TSC2 (16). mechanism for HIF induction through loss of REDD1. Furthermore, Multiple studies have also implicated REDD1 in regulation of they define REDD1 as a key metabolic regulator that suppresses ROS (13, 17), yet the role and significance of REDD1-regulated tumorigenesis through distinct effects on mTORC1 activity and ROS has not been clear. mitochondrial function. A growing body of data links REDD1 to tumor suppression. First, REDD1 has been demonstrated to contribute to apoptotic hypoxia | mTOR | mitochondria | breast cancer | tuberous sclerosis cell death in multiple contexts, arguing for a potential role for REDD1 in tumor cell survival (13, 18). Second, REDD1 has been ontrol of cellular metabolism plays an important role in implicated as a possible contributor to the tumor-suppressive Chuman tumorigenesis. Nascent tumor cells must survive a effect of Foxo transcription factors as both a direct (19) and variety of environmental stresses, including hypoxia and energy indirect (18) Foxo transcriptional target. Third, genetic ablation stress, to allow tumor progression (1, 2). A key mediator of these of REDD1 potentiates proliferation and anchorage-independent metabolic adaptations is the hypoxia-inducible factor HIF. HIF is growth selectively under hypoxic conditions, and potently enhances tumorigenic growth in a model system (16). Finally, a heterodimeric transcription factor whose activity is induced in down-regulation of REDD1 expression is observed in a subset of response to hypoxia and which regulates genes that mediate a human cancers (16). It is unknown, however, which functional variety of hypoxia-adaptive functions including the shift to glyco- properties of REDD1 contribute to its potential role in tumor lytic metabolism, enhancement of angiogenesis, and suppression suppression. Using a genetic model, we have uncovered a specific of oxidative phosphorylation (3–5). The HIF family includes three mTORC1-independent mechanism for REDD1-mediated tumor HIFα subunits (HIF-1α, HIF-2α, and HIF-3α) and a common HIF-1β subunit (also known as ARNT). The key role of HIF in human tumorigenesis is underscored by von Hippel–Lindau Author contributions: P.H., A.R.C., D.D.V., Z.M.N., and L.W.E. designed research; P.H., A.R.C., (VHL) tumor suppressor syndrome, which results from germline D.D.V., and Z.M.N. performed research; M.P.D. and D.S. contributed new reagents/analytic VHL tools; P.H., A.R.C., D.D.V., Z.M.N., M.P.D., D.S., and L.W.E. analyzed data; and L.W.E. wrote mutations in , a gene encoding a subunit of a ubiquitin ligase the paper. α complex which targets HIF subunits for oxygen-dependent deg- The authors declare no conflict of interest. radation (6). Other pathways may contribute to HIF dysregulation This article is a PNAS Direct Submission. in different cancer settings, as recent work has demonstrated an 1P.H. and A.R.C. contributed equally to this work. important role for aberrant HIF up-regulation in promoting 2To whom correspondence should be addressed. E-mail: [email protected]. tumorigenesis in prostate and other cancers downstream of the This article contains supporting information online at www.pnas.org/cgi/content/full/ PI3K-mammalian TOR complex 1 (mTORC1) pathway (7). 0907705107/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0907705107 PNAS | March 9, 2010 | vol. 107 | no. 10 | 4675–4680 Downloaded by guest on September 26, 2021 suppression. These studies demonstrate that REDD1 inactivation REDD1 in this context induces a hypoxia-dependent increase in induces ROS dysregulation and consequent HIF-1α induction proliferation and anchorage-independentgrowth in vitro (16), and is −/− that promotes tumorigenesis. sufficient to confer tumorigenicity in vivo. Treatment of REDD1 tumors with rapamycin, a potent mTORC1 inhibitor, substantially Results reduces tumor growth in this model, consistent with the view that Up-Regulation of HIF-1α Protein and Increased Glycolytic Metabolism REDD1 loss mediates its effect in vivo at least in part through in REDD1−/− Cells. REDD1 deletion dramatically enhances tumor- dysregulation of mTORC1 activity (Fig. S1A) (20). Expression profiling of the respective wild-type and highly igenesis through an unknown mechanism in immortalized mouse −/− embryonic fibroblasts (MEFs) expressing activated (myristoylated) tumorigenic REDD1 MEF populations, followed by gene set fi AKT (myr-AKT MEFs) (16). We first addressed the requirement enrichment analysis (21), identi ed a prominent gene expression −/− for AKTin this process by testing the tumorigenicity of REDD1 or signature that was associated with glycolysis. In particular, many genes directly regulated by HIF-1α were up-regulated in tumori- wild-type immortalized MEFs expressing a control vector (vector REDD1−/− MEFs) (Fig. 1A). As expected, wild-type vector MEFs never formed genic cells compared with matched wild-type cells (Fig. −/− S1B). Consistent with this finding, HIF-1α protein levels were tumors, whereas the matched REDD1 vectorMEFs formed large, −/− dramatically elevated in these REDD1 cells versus the matched rapidly growing tumors in 100% of mice (Fig. 1A). Thus, loss of wild-type cells, under both normoxia and hypoxia (Fig. 1 B and C). Of note, levels of HIF-2α mRNA were more than 50-fold lower than those of HIF-1α in these cells (Fig. S1C). HIF-1α dysregu- A B lation in tumorigenic MEFs was associated with substantial up- ) 3 control rapa regulation of multiple direct HIF-1α target genes (Fig. 1D). Fur- REDD1+/+ REDD1 +/+ -/- +/+ -/- 4000 thermore, HIF dysregulation induced by REDD1 also occurred in REDD1-/- −/− HIF1α epithelial cells, as REDD1 primary immortalized murine ker- atinocytes exhibited up-regulation of endogenous HIF-1α and 2000 p≤0.0001 α E HC HIF-2 compared with their wild-type counterparts (Fig. 1 ). We initially hypothesized that elevated
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