SET1B drives sustained HIF activity and disease progression in clear cell renal cell carcinoma.

Ortmann, B.; Bertlin, J. A. C.; Seear, R. V.; Arnaiz, E.; Lin, S.; Salman, A. M.; Wilson, L.; Harris, A. L.; Stewart, G. D.; Hepburn, A.; Clare, S.; Robson, C. N. N.; Speak, A. O.; Nathan, J. A.

doi:10.1101/2025.05.13.653699

bioRxiv · 10.1101/2025.05.13.653699

SET1B drives sustained HIF activity and disease progression in clear cell renal cell carcinoma.

Ortmann, B.·Bertlin, J. A. C.·Seear, R. V.·Arnaiz, E.·Lin, S.·Salman, A. M.·Wilson, L.·Harris, A. L.·Stewart, G. D.·Hepburn, A.·Clare, S.·Robson, C. N. N.·Speak, A. O.·Nathan, J. A.

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Abstract

The cellular response to hypoxia is driven by hypoxia-inducible factors (HIFs), which regulate genes involved in glycolysis, angiogenesis, and cell proliferation, as well as inflammation and tumour progression. HIF activation is well-characterised and is primarily regulated by oxygen-dependent prolyl hydroxylation and subsequent degradation. However, how transcription of individual HIF target genes is regulated at the chromatin level is less clear. SET1B, a histone H3 lysine 4 (H3K4) methyltransferase, has emerged as a key modulator of HIF target gene transcription. Our study reveals that SET1B interacts with RNA Polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains. We also show that in clear cell renal cell carcinoma (ccRCC), SET1B is critical for sustained HIF activity, and SET1B expression correlates with disease progression and metastasis in patient samples. Moreover, SET1B depletion enhances the efficacy of HIF-2 inhibitors, establishing SET1B as a potential therapeutic target in ccRCC.

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Ortmann, B., Bertlin, J. A. C., Seear, R. V., Arnaiz, E., Lin, S., Salman, A. M., Wilson, L., Harris, A. L., Stewart, G. D., Hepburn, A., Clare, S., Robson, C. N. N., Speak, A. O., Nathan, J. A.. 2025-05-14. SET1B drives sustained HIF activity and disease progression in clear cell renal cell carcinoma.. https://doi.org/10.1101/2025.05.13.653699

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