| First Author | Singhal R | Year | 2021 |
| Journal | J Clin Invest | Volume | 131 |
| Issue | 12 | PubMed ID | 33914705 |
| Mgi Jnum | J:308502 | Mgi Id | MGI:6729838 |
| Doi | 10.1172/JCI143691 | Citation | Singhal R, et al. (2021) HIF-2alpha activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron. J Clin Invest 131(12) |
| abstractText | Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, and metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factors hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha. Our work demonstrates that HIF-2alpha is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2alpha. To overcome this limitation, we performed a small molecule screen to identify HIF-2alpha-dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2alpha-expressing tumor enteroids. Our work demonstrated that HIF-2alpha integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2alpha upregulated lipid and iron regulatory genes in CRC cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Second, via an iron-dependent, lipid peroxidation-independent pathway, HIF-2alpha activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2alpha decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2alpha that can be leveraged for CRC treatment. |
