Targeting Glioblastoma Stem Cells through Disruption of the Circadian Clock

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 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. 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 specifi cally disrupted cancer stem cell growth and self-renewal.

Insights About Circadian Clock and Molecular Pathogenesis in Gliomas

“…The Targeting CLOCK or BMAL1, reduced the expression of the tricarboxylic acid cycle enzymes as well as attenuated mitochondrial metabolic function. Finally, the combinatorial use of CRY and REV-ERB agonists revealed a synergistic antitumor activity against GSCs (138). This study set the stage for considering the role of epigenetic modulations in gliomagenesis.…”

Copy Number Variation and Transcription Regulation of Genes and Immune Microenvironment of Tumor Affect the Stemness of Prostate Cancer Cell

“…PUM1 regulated the expression of hematopoietic stem cells [65] and promoted the migration of cancer cells [45]. CLOCK regulated the biological clock of cancer stem cells and promoted the self-renewal of cancer cells [66]. HMGCS1 could promote cancer development [67] and affect the function of NK cells [68].…”

Circadian Genes as Therapeutic Targets in Pancreatic Cancer

“…These genes are necessary for GSCs proliferation and survival, but they are not required for differentiated glioblastoma cells or normal neural stem cells. In GSCs, the clock machinery seems to regulate glucose metabolism and lipid synthesis, while this control is not exerted in normal neural stem cells, being these differences attributed to distinctive changes in chromatin (92). Both cases show the relevance of circadian programming in CSCs, and, although it is still poorly understood, they reflect how is the reprogramming of the circadian regulation, rather than the rhythm itself, what is needed to understand in CSCs and cancer in order to use the circadian clock as target or tool for therapies.…”