Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

摘要: Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSC). Here, we show that GSCs, differentiated (DGC), and nonmalignant brain cultures all displayed robust circadian rhythms, yet GSCs alone exquisite dependence on core clock transcription factors, BMAL1 CLOCK, for optimal cell growth. Downregulation of or CLOCK in induced cell-cycle arrest apoptosis. Chromatin immunoprecipitation revealed preferentially bound metabolic genes was associated with active chromatin regions compared neural cells. Targeting attenuated mitochondrial function reduced expression tricarboxylic acid cycle enzymes. Small-molecule agonists two independent BMAL1-CLOCK negative regulators, the cryptochromes REV-ERBs, downregulated factors GSC Combination cryptochrome REV-ERB synergistic antitumor efficacy. Collectively, these findings co-opt regulators beyond canonical circuitry to promote stemness maintenance metabolism, offering novel therapeutic paradigms. SIGNIFICANCE: Cancer malignant tumor-cell populations. We demonstrate selectively depend increased binding promoting tumor metabolism. Supporting clinical relevance, pharmacologic targeting networks specifically disrupted cancer growth self-renewal.This article is highlighted In This Issue feature, p. 1469.