Simran Kaur ‘20

All living organisms have circadian rhythms, an approximately twenty-four cycle that ensures the appropriate timing of important physiological functions such as digestion and sleep. Glioblastoma stem cells (GSCs) that are involved in the formation of aggressive brain tumors are stimulated by altered circadian clocks. Clock genes are responsible for the oscillation of gene expression within the day and can behave as both oncogenes and tumor suppressors. A higher incidence of tumors is associated with disturbances in the circadian clock, either due to lifestyle or mutations within clock-genes. 

The clock genes BMAL1 and CLOCK are necessary for the proliferation and survival of GSCs in vitro. Circadian reprogramming, the process of change in the circadian-clock output and clock-controlled genes, is sustained through varying waves of oscillation. This study found that the circadian-output of GSCs includes genes specific to lipid synthesis and glucose metabolism, changes in which have been known to advance the progression of cancer. It was also observed that in the absence of the two clock genes, the metabolic capacity of GSCs dramatically changed. Alterations in chromatin directs circadian reprogramming; GSCs have significantly greater regions of open chromatin, allowing for the clock genes to act as oncogenes and regulate the expression of genes involved in lipid metabolism. Changes in lipid metabolism, which control the expression of proteins and genes in signaling pathways, have been linked to carcinogenic effects in cells. 

In the final portion of the study, researchers used mice models that were altered to carry GSCs to demonstrate that BMAL1-repressive molecules inhibit the self-renewing quality and proliferation of GSCs. One key finding was that the mice that were administered these molecules survived for longer than the mice that were not. The findings of this experiment, however, cannot be translated to humans because of the fact that circadian reprogramming does not occur solely in the brain, but also across the other organ systems. Manipulation of the circadian clock can systematically affect other physiological processes and therefore cause damage to healthy tissue. Future safer and more specific studies are necessary to clearly determine the role of circadian reprogramming in the progression of cancer cells. 

References:

1. G. Solanas and S.A Benitah, Alterations to the Circadian Clock Make Brain Tumours Vulnerable. Nature, (2019). doi: 10.1038/d41586-019-03042-0
2. Image retrieved from: https://pixabay.com/illustrations/time-time-management-stopwatch-3222267/