BMAL1-HIF2α heterodimers contribute to ccRCC
Rebecca M Mello1,2, Diego Gomez Ceballos1,2, Colby R Sandate3
1Department of Molecular and Cellular Biology, Scripps Research Institute, La Jolla, CA, 92037, USA.
Research Square
|July 29, 2024
Summary
Clear cell renal cell carcinoma (ccRCC) cells utilize the circadian gene BMAL1 to drive tumor growth. Targeting BMAL1-HIF2α may offer new therapeutic strategies for ccRCC by enhancing drug sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Chronobiology
Background:
- Circadian disruption is linked to increased cancer risk.
- Tumors often display disrupted circadian gene expression.
- Clear cell renal cell carcinoma (ccRCC) shows robust rhythmic gene expression.
Purpose of the Study:
- Investigate the role of the circadian gene BMAL1 in ccRCC.
- Determine the interaction between BMAL1 and HIF2α in ccRCC.
- Evaluate the therapeutic potential of targeting the BMAL1-HIF2α pathway.
Main Methods:
- Analysis of gene expression in ccRCC tissues and cell lines.
- CRISPR-mediated depletion of BMAL1.
- Chromatin immunoprecipitation assays.
- Assessment of ccRCC cell growth in vitro and in vivo xenografts.
- Drug sensitivity assays using a HIF2α antagonist (PT2399).
Main Results:
- BMAL1 expression is elevated in ccRCC compared to healthy kidneys.
- BMAL1 forms a functional heterodimer with HIF2α, regulating a subset of HIF2α target genes.
- BMAL1 depletion reduces ccRCC growth and reprograms HIF2α activity.
- Higher BMAL1 levels correlate with sensitivity to HIF2α antagonists.
- The BMAL1-HIF2α complex is more sensitive to PT2399 than the ARNT-HIF2α complex.
Conclusions:
- An alternative BMAL1-HIF2α complex contributes to ccRCC growth and HIF2α activity.
- BMAL1-HIF2α is a potential therapeutic target in ccRCC.
- Targeting BMAL1 can sensitize ccRCC cells to HIF2α antagonist drugs.
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