BMAL1-HIF2α heterodimers contribute to ccRCC

Area of Science:

• Oncology
• Molecular Biology
• Chronobiology

Background:

• Circadian disruption is linked to increased cancer risk.
• Tumors often display disrupted circadian gene expression patterns.
• Clear cell renal cell carcinoma (ccRCC) shows robust rhythmic gene expression, with elevated BMAL1 levels.

Purpose of the Study:

• To investigate the role of the circadian gene BMAL1 in ccRCC.
• To determine the functional interaction between BMAL1 and HIF2α in ccRCC.
• To explore the therapeutic potential of targeting the BMAL1-HIF2α pathway.

Main Methods:

• Analysis of gene expression in ccRCC and healthy kidney tissues.
• Investigating the interaction between BMAL1 and HIF2α using cell culture models.
• Depletion of BMAL1 and assessment of its effects on ccRCC cell growth and gene expression.
• Evaluating the sensitivity of ccRCC xenografts to HIF2α antagonists.
• Assessing the impact of BMAL1 levels on drug sensitivity.

Main Results:

• BMAL1 is upregulated 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 alters HIF2α chromatin association.
• Higher BMAL1 expression correlates 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 activity.
• BMAL1 plays a significant role in ccRCC pathogenesis.
• Targeting the BMAL1-HIF2α interaction could be a viable therapeutic strategy for ccRCC, enhancing sensitivity to HIF2α antagonists.