Researchers discover an unexpected place for the clock gene in prostate cancer progression

Our biological or circadian clock synchronizes our bodily processes to natural light and dark rhythms. No wonder then that disturbing the clock can damage our body. In fact, studies have shown that when circadian rhythms are disturbed by sleep deprivation, weak jet, or shift work, some cancers have a higher frequency including prostate cancer, which is like the second leading cause of cancer death for men in the US.

With a desperate need to develop novel therapeutic targets for prostate cancer, researchers at Sidney Kimmel – Jefferson Health (SKCC) studied the circadian clock and found an unexpected place for the CRY-clock gene. 1 in cancer progression. The study was published on January 15 in Nature Communication.

“When we analyzed human cancer data, it was found that the circadian factor CRY-1 increased in prostate cancers at a late stage, and is strongly associated with adverse outcomes,” Karen explained. Knudsen, MBA PhD, executive vice president of oncology services for Jefferson Health and director of the SKCC campaign, and senior author of the study. “However, the role of CRY-1 in human cancers has not been studied.”

Common treatment for prostate cancer involves removal of the male hormone androgen and / or androgen receptor, as prostate tumors require androgens to develop and progress to progressive disease. With their colleagues in the US and Europe, the researchers found that CRY-1 is stimulated by the androgen receptor in the prostate tumor tissue obtained from patients, thus explaining that the level of elevated levels of CRY-1 observed in human disease.

This was clear evidence of the link of CRY-1 to prostate cancer. As we looked further into the role of CRY1, we suddenly found that the circadian factor was altering the way cancer cells repair DNA. “

Ayesha Shafi, PhD, First Author Study, Postdoctoral Researcher, Dr. Knudsen Lab

Cancer treatments aim to damage the DNA in cancer cells and cause deficiencies in repair techniques; eventually the cells self-destruct when the damage is severe. The researchers examined the potential role of CRY-1 in DNA repair in cultured cells, animal models and tissue obtained from prostate cancer patients. They first introduced DNA damage by exposing cancer cells to radiation and found that CRY-1 levels were elevated, indicating that it was responsive to this type of damage. They also found that CRY-1 directly regulates the availability of factors necessary for the DNA repair process, and alters the ways in which cancer cells respond to DNA damage. The findings suggest that CRY-1 may offer a protective effect against destructive therapies.

“The fact that CRY-1 has increased late-stage prostate cancer may explain why androgen-targeted therapies become ineffective at later stages,” said Dr. Shafi. “It also tells us that if a tumor has high levels of CRY-1, targeted DNA repair treatment may not be as effective for them.”

“Not only have we defined a place for CRY-1 outside of its canonical role in circadian rhythms, Dr. Shafi’s findings are the first to reveal the ways in which CRY1 contributes to aggressive disease, “Dr Knudsen adds. “It is interesting that the pro-tumor activities of CRY1 could be operational targets for the treatment of prostate cancer, and this is a guide that will explore Dr. Shafi’s future work.”

Looking ahead, the team plans to explore how best to target and prevent CRY-1 and what other medications may work homogenously to prevent it. on DNA repair in prostate cancer cells. They also plan to study more circadian rhythm genes and find out how circadian disorder 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 providing medication at certain times of the day can be beneficial,” explained Dr. Knudsen. “Our findings open up a number of important research questions examining the link between the circadian clock and cancer. “