2. Academic Validation
  3. BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma

BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma

  • Nat Commun. 2025 Jul 1;16(1):5834. doi: 10.1038/s41467-025-60904-0.
Rebecca M Mello 1 2,  Diego Gomez Ceballos 1 2,  Colby R Sandate 3,  Sicong Wang 1 2,  Celine Jouffe 4 5,  Daniel Agudelo 4,  Nina Henriette Uhlenhaut 4 6,  Nicolas H Thomä 3,  M Celeste Simon 7 8,  Katja A Lamia 9 10
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, USA.
  • 2 Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, USA.
  • 3 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 4 Institute for Diabetes and Endocrinology (IDE), Helmholtz Munich, Neuherberg, Germany.
  • 5 Institute for Diabetes and Cancer (IDC), Helmholtz Munich, Neuherberg, Germany.
  • 6 Metabolic Programming, TUM School of Life Sciences & ZIEL Institute for Food and Health, Freising, Germany.
  • 7 Perelman School of Medicine, Abramson Family Cancer Research Institute, Philadelphia, PA, USA.
  • 8 Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
  • 9 Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, USA. klamia@scripps.edu.
  • 10 Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, USA. klamia@scripps.edu.
PMID: 40595592 DOI: 10.1038/s41467-025-60904-0
Abstract

Circadian disruption enhances Cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). The core circadian transcription factor BMAL1 is closely related to ARNT, and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 selectively reduces HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by a HIF2α antagonist (PT2399). BMAL1-HIF2α is more sensitive than ARNT-HIF2α is to suppression by PT2399, and the effectiveness of PT2399 for suppressing xenograft tumor growth in vivo depends on the time of day at which it is delivered. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 influences HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.

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