Mello Rebecca M, Gomez Ceballos Diego, Sandate Colby R, Wang Sicong, Jouffe Celine, Agudelo Daniel, Uhlenhaut Nina Henriette, Thomä Nicolas H, Simon M Celeste, Lamia Katja A
Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, USA.
Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, USA.
Nat Commun. 2025 Jul 1;16(1):5834. doi: 10.1038/s41467-025-60904-0.
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.
昼夜节律紊乱会增加患癌风险，许多肿瘤都表现出昼夜节律基因表达紊乱。我们发现，在透明细胞肾细胞癌（ccRCC）中，节律性基因表达出人意料地强劲。核心昼夜节律转录因子BMAL1与ARNT密切相关，我们发现BMAL1-HIF2α在ccRCC细胞中调节HIF2α靶基因的一个子集。BMAL1的缺失选择性地降低了HIF2α与染色质的结合及靶基因表达，并减少了ccRCC在培养物中和异种移植中的生长。对现有数据的分析显示，在对HIF2α拮抗剂（PT2399）的生长抑制敏感的患者来源异种移植中，BMAL1水平更高。BMAL1-HIF2α比ARNT-HIF2α对PT2399的抑制更敏感，并且PT2399在体内抑制异种移植肿瘤生长的有效性取决于给药的时间。这些发现共同表明，含有昼夜节律伴侣BMAL1的另一种HIF2α异二聚体影响ccRCC细胞中HIF2α的活性、生长以及对HIF2α拮抗剂药物的敏感性。
