Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factor hypoxia-inducible factor (HIF)-1α and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult and tumors rapidly acquire resistance to recently developed inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α expressing tumor enteroids. Our work demonstrates that HIF-2α integrates two independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upreguated lipid and iron regulatory genes in colon cancer cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Secondly, via an iron dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS, via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrate a mechanistic vulnerability in cancer cells that were the dependent on HIF-2α that can be leveraged for colon cancer treatment.
Rashi Singhal, Sreedhar R. Mitta, Nupur K. Das, Samuel A. Kerk, Peter Sajjakulnukit, Sumeet Solanki, Anthony Andren, Roshan Kumar, Kenneth P. Olive, Ruma Banerjee, Costas A. Lyssiotis, Yatrik M. Shah
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