Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock
Menée in vitro et à l'aide d'une xénogreffe de glioblastome sur un modèle murin, cette étude met en évidence l'intérêt d'une stratégie thérapeutique consistant à réduire la croissance des cellules souches cancéreuses en ciblant des facteurs de transcription impliqués dans la régulation de l'horloge circadienne
Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSCs). Here, we show that GSCs, differentiated glioblastoma cells (DGCs), and non-malignant brain cultures all displayed robust circadian rhythms, yet GSCs alone displayed exquisite dependence on core clock transcription factors, BMAL1 and CLOCK, for optimal cell growth. Downregulation of BMAL1 or CLOCK in GSCs induced cell cycle arrest and apoptosis. Chromatin immunoprecipitation revealed BMAL1 preferentially bound at metabolic genes in GSCs, associated with differences in active chromatin regions compared to NSCs. Targeting BMAL1 or CLOCK attenuated mitochondrial metabolic function and reduced expression of the tricarboxylic acid (TCA) cycle enzymes. Small molecule agonists of two independent BMAL1::CLOCK negative regulators, the Cryptochromes and REV-ERBs, downregulated stem cell factors and reduced GSC growth. Combination of Cryptochrome and REV-ERB agonists induced synergistic anti-tumor efficacy. Collectively, GSCs coopt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms.
Cancer Discovery 2019