Cancer discovery, 2019-11, Vol.9 (11), p.1556-1573
2019
Details
- Autor(en) / Beteiligte
- Titel
- Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock
- Ist Teil von
- Cancer discovery, 2019-11, Vol.9 (11), p.1556-1573
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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 or 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 or 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. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2159-8274eISSN: 2159-8290DOI: 10.1158/2159-8290.cd-19-0215Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6983300
- Format
- –
- Schlagworte
- Animals, ARNTL Transcription Factors - genetics, Brain Neoplasms - drug therapy, Brain Neoplasms - genetics, Cell Line, Tumor, Circadian Clocks - drug effects, Citric Acid Cycle - drug effects, CLOCK Proteins - genetics, Drug Synergism, Gene Expression Regulation, Neoplastic - drug effects, Glioblastoma - drug therapy, Glioblastoma - genetics, Humans, Mice, Neoplastic Stem Cells - chemistry, Neoplastic Stem Cells - drug effects, Small Molecule Libraries - administration & dosage, Small Molecule Libraries - pharmacology, Up-Regulation, Xenograft Model Antitumor Assays