An unexpected and new target for prostate cancer: our biological clock

Our biological or circadian clock synchronizes all of our bodily processes to the natural rhythms of light and dark. So it’s no wonder that disrupting the clock can wreak havoc on our bodies. In fact, studies have shown that when circadian rhythms are disrupted by sleep deprivation, jet lag, or shift work, there is an increased incidence of certain cancers, including prostate cancer, which is the second largest. cause of cancer death in men in the United States. urgent need to develop new therapeutic targets for prostate cancer, researchers at Sidney Kimmel Cancer – Jefferson Health (SKCC) explored the circadian clock and discovered an unexpected role of the CRY-1 clock gene in cancer progression. The study was published on January 15 in Nature communications.

“When we analyzed data on human cancer, circadian factor CRY-1 was found to increase in advanced prostate cancers and is strongly associated with poor outcomes,” says Karen Knudsen, MBA Ph.D. ., executive vice president of oncology services for Jefferson Health and corporate director of SKCC, and lead author of the study. “However, the role of CRY-1 in human cancers has not been explored.”

A common therapy for prostate cancer is to suppress the male hormone androgen and / or the androgen receptor, since prostate tumors require androgens to grow and progress to advanced disease. Together with their collaborators in the United States and Europe, the researchers discovered that CRY-1 is induced by the androgen receptor in prostate tumor tissue obtained from patients, thus partly explaining the high levels of CRY-1 observed. in human disease.

“It was a clear indication of CRY-1’s link to prostate cancer,” says Ayesha Shafi, Ph.D., a postdoctoral researcher in Dr. Knudsen’s lab and first author of the study. “As we deepened our study of the role of CRY1, we unexpectedly discovered that the circadian factor alters the way cancer cells repair DNA.

Cancer treatments aim to damage the DNA of cancer cells and cause defects in repair mechanisms; eventually, cells self-destruct when damage is severe. The researchers investigated the possible role of CRY-1 in DNA repair in cultured cells, animal models, and tissues taken from patients with prostate cancer. They first induced DNA damage by exposing cancer cells to radiation and found that CRY-1 levels were high, indicating that it was responding to this type of damage. They also found that CRY-1 directly regulates the availability of factors essential to the DNA repair process and alters the ways in which cancer cells respond to DNA damage. The results suggest that CRY-1 may offer a protective effect against damaging therapies.

“The fact that CRY-1 is elevated in advanced prostate cancer may explain why androgen targeting treatments become ineffective in these later stages,” says Dr Shafi. “It also tells us that if a tumor has high levels of CRY-1, treatments targeting DNA repair may be less effective for it.”

“Not only have we described a role for CRY-1 outside of its canonical function in circadian rhythms, but Dr. Shafi’s findings are the first to reveal ways in which CRY1 contributes to aggressive disease,” adds Dr. Knudsen . “It should be noted that the pro-tumor functions of CRY1 may be viable targets for treating prostate cancer, and this is a direction that Dr. Shafi’s future work will explore.”

Going forward, the team plans to explore how best to target and block CRY-1 and what other existing therapies could work synergistically to hinder DNA repair in prostate cancer cells. They also plan to study more circadian rhythm genes and determine how the circadian disruption may affect cancer treatment.

“It has been shown that circadian disturbances can affect the effectiveness of treatment, but also that aligning treatment with the body’s natural rhythms or giving treatment at certain times of the day can be beneficial,” explains Dr Knudsen. “Our findings open up a host of important research questions exploring the link between the circadian clock and cancer.”