A recent study on mice points to a previously unknown link as a likely culprit behind increased lung cancer tumor burden.
Interview by Alyx Arnett
Chronic circadian disruption—such as that experienced by rotating shift workers—has been linked to increased cancer risk, but the biological mechanisms that underpin this risk remain largely unknown.
At Scripps Research, Katja Lamia, PhD, associate professor in the department of molecular medicine, and co-investigators studied mice with the most commonly mutated gene in lung cancer, housed in either a normal light cycle, or in a light cycle designed to imitate the effects of rotating shift work or frequent eastbound transmeridian flights.
As expected, the mice exposed to the rotating shift work light pattern had an increased tumor burden, but RNA sequencing revealed a surprise culprit. The increased number of tumors was tied to a previously unknown mechanism of action linked to circadian disruption: the heat shock factor 1 (HSF1) family of proteins.
The researchers suspect that HSF1 activity is heightened in response to circadian disruption, as changes in sleep cycles disturb the daily rhythms of body temperature.
Lamia discussed the study with Sleep Review over email. The transcript has been lightly edited for clarity and style.
[Editor’s Note: Read the full study, Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer, in Science Advances.]
What led you to investigate the link between circadian disruption and cancer growth?
My lab is determining how disruptions in circadian cycles impact health and disease. It has been long known that shift workers and others who experience circadian disruption regularly are at greater risk of diseases like cancer, but it hasn’t been well understood. With our recent study, we wanted to finally reveal the molecular link between chronic circadian disruption and tumor growth.
Were there any surprising discoveries?
In the mice that experienced chronic jet lag, we were surprised to find that heat shock factor 1 (HSF1)-driven gene expression was increased. HSF1 protects cells during extreme temperature changes by activating genes that make sure proteins are still folded and distributed properly throughout the cell. While HSF1-driven genes have been linked to cancer in the past, this is the first time they’ve been linked to circadian disruption.
Can you expand on how the HSF1 family of proteins is the main culprit in cancer growth in response to circadian disruption?
We’re currently conducting additional studies to figure out if HSF1 signaling is required to increase tumor burden. We now know there is a correlation, but we need to prove there is a causation. One hypothesis is that our bodies have a very natural temperature rhythm, where our internal temperature drops by a few degrees when we sleep. With shift workers, these natural temperature cycles could be disrupted, and they may not experience that cyclical body temperature drop. HSF1 genes are very sensitive to temperature changes and cycles, so this could be the reason it’s all connected.
How do you envision your findings being applied to cancer treatment and prevention in the future?
If our hypothesis is correct, there is the opportunity to monitor the body temperature of shift workers and optimize their work schedules so they are experiencing these natural temperature drops. This could offer a noninvasive, proactive way of protecting shift workers against potential cancer growth.
What further research needs to be done?
We are continuing to study if HSF1 signaling is the main driver of cancer growth when circadian rhythm is disrupted. We are now looking at models in which we delete the HSF1 gene to see if that prevents tumor formation.
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