Circadian Clock Alters Rhythms of Cancer-Related Genes

Circadian Clock Alters Rhythms of Cancer-Related Genes
engineer using digital tablet working late night shift at petroleum oil refinery in industrial estate.

Shift or night work is known to raise the risk of health problems including obesity, cardiovascular disease, and cancer.  A new study from Washington State University Health Sciences Spokane provides some insights into potential mechanisms underlying the risk for cancer.

“There has been mounting evidence that cancer is more prevalent in night shift workers, which led the World Health Organization’s International Agency for Research on Cancer to classify night shift work as a probable carcinogenic,” said co-corresponding author Shobhan Gaddameedhi, an associate professor formerly with the WSU College of Pharmacy and Pharmaceutical Sciences.

The team focused on the fact that cells have their own cellular clock. Genes associated with that clock has a rhythmic nature, expressing certain patterns which vary by day and night. They chose to study the expression of these genes, and known cancer-causing genes, in leukocytes (white blood cells) looking for changes that might be disrupted by night shift work.

To recreate and control a simulated work schedule, fourteen volunteers spent a week inside a sleep laboratory. Half completed a simulated three-day night shift; the others, three days of a simulated day shift schedule. At the close of the three-day shifts, workers kept the same routine, including one 24 hour period where they were kept awake under identical conditions. Blood samples were taken every three hours during that 24 hour cycle.

The team studied the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways in the volunteers’ leukocytes. They found that the rhythms of gene expression in cancer pathways in the night shift workers was significantly altered compared with the normal circadian gene rhythms of those working the day shift.

Compounding the cancer risk, a DNA repair pathway was upregulated in the rhythmic genes following a simulated day shift but not after a night shift. And, leukocytes from the night shift workers showed more DNA damage than in the day shift workers.

“Our results suggest that circadian dysregulation of DNA repair may increase DNA damage and potentiate elevated cancer risk in night shift workers,” the authors write.

In functional tests, there was an increased sensitivity to both endogenous and exogenous sources of DNA damage after exposure to simulated night shift.

After the researchers exposed isolated white blood cells to ionizing radiation at two different times of day, cells that were radiated in the evening showed increased DNA damage in the night shift condition as compared to the day shift condition. This meant that white blood cells from night shift participants were more vulnerable to external damage from radiation, a known risk factor for DNA damage and cancer.

“Taken together, these findings suggest that night shift schedules throw off the timing of expression of cancer-related genes in a way that reduces the effectiveness of the body’s DNA repair processes when they are most needed,” said co-corresponding author Jason McDermott, a computational scientist with the Pacific Northwest National Laboratory’s Biological Sciences Division.

The next step is to conduct the same experiment with real-world shift workers who have been consistently on day or night shifts for many years to determine whether in night workers the unrepaired DNA damage builds up over time.

These findings may also have relevance for timing cancer therapy during chronotherapy. With this approach, treatment is delivered based on the idea that administering medications at different times of the circadian cycle will minimize side effects and maximize therapeutic effects. Clinical trials have shown that both can vary widely depending on the time of drug administration in relation to circadian rhythm.