HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron

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 1 alpha (HIF-1 alpha) and HIF-2 alpha. Our work demonstrates that HIF-2 alpha is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2 alpha. To overcome this limitation, we performed a small molecule screen to identify HIF-2 alpha -dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2 alpha- expressing tumor enteroids. Our work demonstrated that HIF-2 alpha integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2 alpha 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-2 alpha activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2 alpha 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-2 alpha that can be leveraged for CRC treatment.