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Lookup NU author(s): Dr Brian OrtmannORCiD, Lukasz Marzec, Alexander Handyside, Laura WilsonORCiD, Dr Anastasia Hepburn, Professor Craig RobsonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
©2026 The Authors; Published by the American Association for Cancer Research. The cellular response to hypoxia is driven by hypoxia-inducible factors (HIF), 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 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. In this study, 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 is critical for sustained HIF activity, and SET1B expression correlated with disease progression and metastasis in patient samples. Moreover, SET1B depletion enhanced the efficacy of HIF2 inhibitors. These findings establish SET1B as a driver of tumor progression and potential therapeutic target in ccRCC. SIGNIFICANCE: SET1B functions as a key regulator of HIF-dependent transcription and cancer growth under low-oxygen conditions, revealing a therapeutic target to enhance treatment efficacy and potentially slow disease progression in kidney cancer.
Author(s): Ortmann BM, Pauzaite T, Bertlin JAC, Seear RV, Arnaiz E, Marzec LW, Handyside A, Bowker LM, Barnett SE, Harcourt K, Lin S, Salman AM, Wilson L, Harris AL, Stewart GD, Hepburn A, Clare S, Robson CN, Coulson JM, Speak AO, Nathan JA
Publication type: Article
Publication status: Published
Journal: Cancer Research
Year: 2026
Volume: 86
Issue: 15
Pages: 3704-3719
Online publication date: 04/08/2026
Acceptance date: 30/03/2026
Date deposited: 17/08/2026
ISSN (print): 0008-5472
ISSN (electronic): 1538-7445
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/0008-5472.CAN-25-1076
DOI: 10.1158/0008-5472.CAN-25-1076
Data Access Statement: The mRNA expression data for SET1B in KIRC were obtained from TCGA database, more specifically OncoLnc (http://www.oncolnc.org/), and analyzed by comparing the top 25% and bottom 25% of SET1B mRNA expression levels within the patient cohort. All raw data generated during this study are available from the corresponding author upon reasonable request.
PubMed id: 41941749
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