Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

Glioblastoma stem cells (GSCs) exhibit a strong dependence on circadian clock proteins BMAL1 and CLOCK for optimal growth.

• GSCs, differentiated glioblastoma cells, and nonmalignant brain cultures all demonstrate robust circadian rhythms.
• Downregulation of BMAL1 and CLOCK in GSCs leads to cell-cycle arrest and apoptosis.
• BMAL1 preferentially binds to metabolic genes in GSCs, indicating a role in regulating tumor metabolism.
• Targeting BMAL1 and CLOCK negatively impacts mitochondrial function and reduces tricarboxylic acid cycle enzyme expression.
• Small-molecule agonists targeting negative regulators of BMAL1 and CLOCK decrease stem cell factors and inhibit GSC growth.
• Combining agonists of cryptochromes and REV-ERBs shows a synergistic effect in reducing tumor growth.

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