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Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134974 | GEO | 2019/10/24

REPOSITORIES: GEO

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Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock.

Project description: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.

| S-EPMC6983300 | biostudies-literature

Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock [RNA-Seq]

Project description:Glioblastomas are highly lethal cancers, containing self-renewing glioblastoma stem cells (GSCs). Here, we show that GSCs, differentiated glioblastoma cells (DGCs), and normal 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.

2019-10-24 | GSE134973 | GEO

Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock [ChIP-Seq]

2019-10-24 | GSE134972 | GEO

Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

Project description:Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

| PRJNA556901 | ENA

Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock [ChIP-Seq]

Project description:Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock [ChIP-Seq]

| PRJNA556900 | ENA

Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock [RNA-Seq]

Project description:Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock [RNA-Seq]

| PRJNA556903 | ENA

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Project description:This SuperSeries is composed of the SubSeries listed below.

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