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HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron
Open accessAbstract
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 1α (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 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 demonstrated that HIF-2α integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α 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-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 demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2α that can be leveraged for CRC treatment.
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“Belzutifan has also demonstrated significant efficacy in heavily pretreated metastatic RCC suggesting that HIF-2α inhibition might also offer an effective treatment for advanced ccRCC [91].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [91]
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“Belzutifan has also demonstrated significant efficacy in heavily pretreated metastatic RCC suggesting that HIF-2α inhibition might also offer an effective treatment for advanced ccRCC [91].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [91]
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“235 Similarly, the activation of HIF2 α increases hypoxia-inducible lipid droplet-associated protein (HILPDA) expression, driving the accumulation of PUFAs and subsequent lipid peroxidation, which contributes to the vulnerability of clear-cell carcinomas to ferroptosis.”
BackgroundHypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer
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“HIF-2 α activation in colorectal cancer upregulates genes involved in lipid and iron metabolism, resulting in enhanced susceptibility to dimethyl fumarate-induced ferroptosis 175 .”
BackgroundBell, H. N., Rebernick, R. J., Goyert, J. W., Singhal, R., Kuljanin, M., Kerk, S. A., Huang, W., Das, N. K., Andren, A. C., Solanki, S. A., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.12.001 · Cited by 310
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“Increased production or stimulation of ROS can induce lipid peroxidation, resulting in various forms of RCD [14–16].”
BackgroundRevisiting the HIF switch in the tumor and its immune microenvironment.
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Metadata
- Authors
- Singhal, R., Mitta, S. R., Das, N. K., Kerk, S. A., Sajjakulnukit, P., Solanki, S., Andren, A., Kumar, R., Olive, K. P., Banerjee, R., Lyssiotis, C. A., & Shah, Y. M.
- Affiliations
- U-M Rogel Cancer Center (US)
- University of Michigan (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Shah, Yatrik M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-06-15
- Volume
- 131
- Issue
- 12
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8203462
- OpenAlex
- W3159210359
- Semantic Scholar
- 87392476cf734f17c13d3774c49b2d48506dbe37
- Cited by
- 215
- References
- 67
- Citations by year
- 2026: 36 · 2025: 47 · 2024: 41 · 2023: 43 · 2022: 39 · 2021: 9
- FWCI
- 21.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01CA148828,R01CA245546,R01DK095201,R01CA244931,R35GM130183,P50CA130810,P30CA046592,DK034933,DK097153)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- HIF-2α, colorectal cancer, ferroptosis, oxidative cell death, hypoxia, reactive oxygen species, cysteine oxidation, dimethyl fumarate, synthetic lethality, HIF-2α inhibitor
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Humans, Iron, Mice, Transgenic, Neoplasm Proteins, Oxidation-Reduction, Colorectal Neoplasms, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Cell Death, Reactive Oxygen Species, HT29 Cells, HCT116 Cells, Mice, Basic Helix-Loop-Helix Proteins
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