Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis

Callahan, R. C.; Bhagavatula, G.; Curry, J.; Staley, A. W.; Schaefer, R. E. M.; Minhajuddin, F.; Zhou, L.; Neuhart, R.; Atif, S. M.; Orlicky, D. J.; Cartwright, I. M.; Gerich, M.; Theiss, A. L.; Hall, C. H.; Colgan, S. P.; Onyiah, J. C.

doi:10.1101/2024.03.06.583112

bioRxiv · 10.1101/2024.03.06.583112

Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis

Callahan, R. C.·Bhagavatula, G.·Curry, J.·Staley, A. W.·Schaefer, R. E. M.·Minhajuddin, F.·Zhou, L.·Neuhart, R.·Atif, S. M.·Orlicky, D. J.·Cartwright, I. M.·Gerich, M.·Theiss, A. L.·Hall, C. H.·Colgan, S. P.·Onyiah, J. C.

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Abstract

Induction of heme oxygenase-1 (HO-1/Hmox1) is broadly considered cytoprotective, but the role of colonic epithelial HO-1 in colitis-associated tumorigenesis is poorly defined. HO-1 catabolizes heme, releasing ferrous iron, a key driver of oxidative stress and lipid peroxidation. We observed that colonic epithelial HO-1 is induced during colitis and tumorigenesis. We also found that HO-1 is upregulated in ferroptosis-inducing conditions in murine and human colonic epithelial organoids, and correlated with lipid peroxidation and ferroptosis markers in colonic tumors. In colonic epithelial organoids exposed to heme, deletion of Hmox1 amplified a compensatory oxidative stress and detoxification transcriptional program, likely reflecting unresolved oxidative and non-oxidative toxicity from heme. In vivo, epithelial HO-1 deficient mice developed significantly fewer and smaller tumors compared to littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from knockout mice exhibited reduced iron levels, decreased lipid peroxidation, lower oxidative DNA damage, and decreased proliferation. Single-cell RNA sequencing of tumor epithelial cells revealed a shift from a proliferative to a stress-adaptive program with loss of HO-1. These findings identify epithelial HO-1 as a context-dependent regulator of tumorigenesis: protective against acute heme toxicity, but promoting iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.

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Callahan, R. C., Bhagavatula, G., Curry, J., Staley, A. W., Schaefer, R. E. M., Minhajuddin, F., Zhou, L., Neuhart, R., Atif, S. M., Orlicky, D. J., Cartwright, I. M., Gerich, M., Theiss, A. L., Hall, C. H., Colgan, S. P., Onyiah, J. C.. 2024-03-10. Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis. https://doi.org/10.1101/2024.03.06.583112

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