Cancer has been associated with disruptions in the circadian rhythm, which describes how our bodies adjust to the 24-hour cycle of light and darkness. Even though shift workers and others with irregular schedules frequently encounter these interruptions, the connection between the two has not been fully understood. But a recent Scripps Research finding is shedding light on what might be driving this correlation. The results, which were published on September 28, 2022, in Science Advances, show that chronic circadian disruption significantly accelerated the growth of lung cancer in animal models. Researchers are shedding light on the enigmatic relationship between our sleep habits and disease by identifying the genes at play. This information could be used to improve monitoring of high-risk groups and come up with more accurate ways to treat cancer.
Our goal for this study, says senior author Katja Lamia, PhD, associate professor in the Department of Molecular Medicine, “was to understand why shift workers and others with disrupted sleep schedules have higher rates of cancer.”
The most frequently mutated gene in lung cancer, KRAS, was expressed in a mouse model to help the researchers respond to this question. A “normal” light cycle, which consists of 12 hours of light and 12 hours of darkness, was used to house half of the mice. The light cycle for the other half of the population was designed to resemble that of shift workers, with the light hours shifting forward by eight hours every two or three days.
The results showed that the researchers’ initial ideas were right: the mice who were exposed to the random, changing light patterns had 68% more tumors.
But when they used RNA sequencing to find the genes that made the cancer spread, they were shocked to find that the main culprit was a group of proteins in the heat shock factor 1 (HSF1) family.
“We were not expecting to find this mechanism in this place. “HSF1 has been demonstrated to increase tumor formation rates in a variety of cancer models, but it has never been associated with circadian disruption,” says Lamia.
When a cell is under extreme stress—in this case, when it experiences temperature changes—HSF1 genes ensure that proteins are still made correctly. The team thinks that changes in our sleep patterns mess up the daily rhythms of our body temperature, which causes HSF1 activity to go up in response to a disruption in our circadian rhythms.
“Normally, when we sleep, our body temperature drops by one or two degrees. If shift workers don’t experience the expected drop, the HSF1 pathway may not function as it should, which could ultimately result in more dysregulation in the body, “adds Lamia. She says that more research needs to be done in this area, but she thinks that cancer cells could use the HSF1 pathway to make mutant proteins that don’t fold properly.
Our understanding of how circadian rhythms affect cancer is shaped by these findings, which may also point the way toward a preventative strategy for safeguarding more vulnerable groups who are at risk. By non-invasively monitoring body temperature, it might be possible to optimize the schedules of shift workers and even stop this kind of dysregulation that can result in cancer.
With these results in hand, researchers are now trying to figure out if HSF1 signaling is actually needed for tumor burden to go up or if it is just a correlation.
We must figure out how they are all related now that we are aware of a molecular connection between HSF1, circadian disruption, and tumor growth, claims Lamia.
