Circadian rhythm disruptions have been linked to cancer but the connection has been poorly understood, even though shift workers and others with irregular schedules experience these disruptions regularly. A new Scripps Research article published in Science Advances shows that chronic circadian disruption significantly increased lung cancer growth in animal models.
By identifying the genes implicated, the researchers are illuminating the mysterious link between sleeping patterns and disease, which could help inform everything from developing more targeted cancer treatments to better monitoring high-risk groups.
“There has always been a lot of evidence that shift workers and others with disrupted sleep schedules have higher rates of cancer, and our mission for this study was to figure out why,” said senior author Katja Lamia, PhD, associate professor in the Department of Molecular Medicine.
The researchers used mice with KRAS genes. Half of the mice were housed in a “normal” light cycle, meaning 12 hours of light and 12 hours of darkness. The other half were housed in a light cycle meant to resemble that of shift workers’, where the light hours were moved earlier by eight hours every two or three days.
The findings agreed with predictions: mice that were exposed to the irregular, shifting light patterns had an increased tumour burden of 68%.
With RNA sequencing, they determined the different genes involved in the cancer growth – and were surprised to discover a subset in the heat shock factor 1 (HSF1) family of proteins.
“This is not the mechanism we were expecting to find here. HSF1 has been shown to increase rates of tumour formation in several different models of cancer, but it has never been linked to circadian disruption before,” Lamia says.
HSF1 genes are responsible for making sure proteins are still made correctly even when a cell is under extreme stress – in this case, when it experiences changes in temperature. The team suspects that HSF1 activity is increased in response to circadian disruption because changes in our sleep cycles disturb the daily rhythms of our bodies’ temperature.
“Normally, our body temperature changes by one or two degrees while we’re sleeping. If shift workers don’t experience that normal drop, it could interfere with how the HSF1 pathway normally operates – and ultimately lead to more dysregulation in the body,” A/Prof Lamia added. She believes cancer cells may exploit the HSF1 pathway to their own benefit and create mutant, misfolded proteins, but says this needs more research.
These findings could potentially point preventative strategies for at-risk groups. By non-invasive monitoring of body temperature, it may be possible to optimise shift workers’ schedules and even halt this type of dysregulation that can lead to cancer. The scientists are now evaluating if HSF1 signalling is required to increase tumour burden and isn’t solely just a correlation.
“Now that we know there’s a molecular link between HSF1, circadian disruption and tumour growth, it’s our job to determine how they’re all connected,” A/Prof Lamia said.
Source: Scripps Research
