Targeting Glioblastoma Stem Cells Through Disruption of the Circadian Clock
Published OnlineFirst August 27, 2019; DOI: 10.1158/2159-8290.CD-19-0215 RESEARCH ARTICLE Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock Zhen Dong1, Guoxin Zhang1, Meng Qu2, Ryan C. Gimple1,3, Qiulian Wu1, Zhixin Qiu1, Briana C. Prager1,3, Xiuxing Wang1, Leo J.Y. Kim1,3, Andrew R. Morton3, Deobrat Dixit1, Wenchao Zhou4, Haidong Huang4, Bin Li5, Zhe Zhu1, Shideng Bao4, Stephen C. Mack6, Lukas Chavez7, Steve A. Kay2, and Jeremy N. Rich1 Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst August 27, 2019; DOI: 10.1158/2159-8290.CD-19-0215 ABSTRACT Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSC). Here, we show that GSCs, differentiated glioblastoma cells (DGC), and nonmalignant 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 immu- noprecipitation revealed that BMAL1 preferentially bound metabolic genes and was associated with active chromatin regions in GSCs compared with neural stem cells. Targeting BMAL1 or CLOCK attenu- ated mitochondrial metabolic function and reduced expression of tricarboxylic acid 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 cryp- tochrome and REV-ERB agonists induced synergistic antitumor effi cacy. Collectively, these fi ndings show that GSCs co-opt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms.
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