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BMAL1-HIF2α heterodimers contribute to ccRCC.
Mello, Rebecca M; Ceballos, Diego Gomez; Sandate, Colby R; Agudelo, Daniel; Jouffe, Celine; Uhlenhaut, Nina Henriette; Thomä, Nicolas H; Simon, M Celeste; Lamia, Katja A.
Afiliación
  • Mello RM; Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Ceballos DG; Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Sandate CR; Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Agudelo D; Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Jouffe C; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • Uhlenhaut NH; Institute for Diabetes and Endocrinology (IDE), Helmholtz Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
  • Thomä NH; Institute for Diabetes and Endocrinology (IDE), Helmholtz Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
  • Simon MC; Institute for Diabetes and Cancer (IDC), Helmholtz Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
  • Lamia KA; Institute for Diabetes and Endocrinology (IDE), Helmholtz Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
Res Sq ; 2024 Jul 16.
Article en En | MEDLINE | ID: mdl-39070610
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). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. 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 reprograms 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). We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasing BMAL1 sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos