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Cancer Discov. 2019 Nov;9(11):1556-1573. doi: 10.1158/2159-8290.CD-19-0215. Epub 2019 Aug 27.

Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock.

Author information

1
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, California.
2
Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California.
3
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
4
Department of Cancer Biology, Center for Cancer Stem Cell Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
5
Ludwig Institute for Cancer Research, La Jolla, California.
6
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
7
Department of Medicine, University of California, San Diego, California.
8
Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California. jerich@ucsd.edu stevekay@usc.edu.
9
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, California. jerich@ucsd.edu stevekay@usc.edu.
#
Contributed equally

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 immunoprecipitation 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 attenuated 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 cryptochrome and REV-ERB agonists induced synergistic antitumor efficacy. Collectively, these findings show that GSCs co-opt circadian regulators beyond canonical circadian circuitry to promote stemness maintenance and metabolism, offering novel therapeutic paradigms. SIGNIFICANCE: Cancer stem cells are highly malignant tumor-cell populations. We demonstrate that GSCs selectively depend on circadian regulators, with increased binding of the regulators in active chromatin regions promoting tumor metabolism. Supporting clinical relevance, pharmacologic targeting of circadian networks specifically disrupted cancer stem cell growth and self-renewal.This article is highlighted in the In This Issue feature, p. 1469.

PMID:
31455674
PMCID:
PMC6983300
[Available on 2020-05-01]
DOI:
10.1158/2159-8290.CD-19-0215

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