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Mello, R.M.* ; Gomez Ceballos, D.* ; Sandate, C.R.* ; Wang, S.* ; Jouffe, C. ; Agudelo, D. ; Uhlenhaut, N.H. ; Thomä, N.H.* ; Simon, M.C.* ; Lamia, K.A.*

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

Nat. Commun. 16:5834 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Hypoxia-inducible Factors; Transcriptional Architecture; Cancer; Clock; Angiogenesis; Atlas; Mop3; Hif
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 5834 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Endocrinology (IDE)
Institute of Diabetes and Cancer (IDC)
POF-Topic(s) 30202 - Environmental Health
30201 - Metabolic Health
Research field(s)
Helmholtz Diabetes Center
PSP Element(s) G-501900-259
G-502594-001
Grants DFG
DFG (German Research Foundation)
DAAD (German Academic Exchange Service) in the context of the Helmholtz Research School for Diabetes
National Center for Advancing Translational Sciences of the National Institutes of Health
National Institutes of Health
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
DOI 10.1038/s41467-025-60904-0
WOS ID 001523451000047
Scopus ID 105009718535
PubMed ID 40595592
Erfassungsdatum 2025-07-03
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