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

Author

Listed:
  • Rebecca M. Mello

    (Scripps Research Institute
    Scripps Research Institute)

  • Diego Gomez Ceballos

    (Scripps Research Institute
    Scripps Research Institute)

  • Colby R. Sandate

    (Friedrich Miescher Institute for Biomedical Research)

  • Sicong Wang

    (Scripps Research Institute
    Scripps Research Institute)

  • Celine Jouffe

    (Helmholtz Munich
    Helmholtz Munich)

  • Daniel Agudelo

    (Helmholtz Munich)

  • Nina Henriette Uhlenhaut

    (Helmholtz Munich
    TUM School of Life Sciences & ZIEL Institute for Food and Health)

  • Nicolas H. Thomä

    (Friedrich Miescher Institute for Biomedical Research)

  • M. Celeste Simon

    (Abramson Family Cancer Research Institute
    University of Pennsylvania)

  • Katja A. Lamia

    (Scripps Research Institute
    Scripps Research Institute)

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.

Suggested Citation

  • Rebecca M. Mello & Diego Gomez Ceballos & Colby R. Sandate & Sicong Wang & Celine Jouffe & Daniel Agudelo & Nina Henriette Uhlenhaut & Nicolas H. Thomä & M. Celeste Simon & Katja A. Lamia, 2025. "BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60904-0
    DOI: 10.1038/s41467-025-60904-0
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