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 tumor progression. HIF activation is well-characterized and is primarily regulated by oxygen-dependent prolyl hydroxylation and subsequent degradation. SET1B, a histone H3 lysine 4 (H3K4) methyltransferase, has recently emerged as a key modulator of HIF target gene transcription, but evidence suggests that it plays a broader role in modulating HIF transcriptional activity beyond histone methylation. Here, we revealed that SET1B interacts with RNA polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains. In clear cell renal cell carcinoma (ccRCC), SET1B was critical for sustained HIF activity, and SET1B expression correlated with disease progression and metastasis in patient samples. Moreover, SET1B depletion enhanced the efficacy of HIF-2 inhibitors. These findings establish SET1B as a driver of tumor progression and potential therapeutic target in ccRCC.
Cancer research. 2026 Apr 06 [Epub ahead of print]
Brian M Ortmann, Tekle Pauzaite, James A C Bertlin, Rachel V Seear, Esther Arnaiz, Lukasz W Marzec, Alexander Handyside, Laura M Bowker, Sarah E Barnett, Katherine Harcourt, Salwa Lin, Ahmed M Salman, Laura Wilson, Adrian L Harris, Grant D Stewart, Anastasia Hepburn, Simon Clare, Craig N Robson, Judy M Coulson, Anneliese O Speak, James A Nathan
Newcastle University Newcastle upon Tyne United Kingdom., University of Cambridge Cambridge United Kingdom., University of Oxford Oxford United Kingdom., Newcastle University Newacstle United Kingdom., Newcastle University United Kingdom., University of Liverpool United Kingdom., University of Liverpool Liverpool United Kingdom., University of Cambridge United Kingdom., Taif University Taif, Western Saudi Arabia., University of Oxford United Kingdom., University of Cambridge Cambridge, Cambridgeshire United Kingdom., Newcastle University Newcastle Upon Tyne, Tyne and Wear United Kingdom., University of Newcastle Newcastle upon Tyne, Tyne and Wear United Kingdom.