Laboratory studies by researchers at the Sidney Kimmel Cancer-Jefferson Health (SKCC) have found an unexpected role for the circadian clock gene CRY1, in prostate cancer progression. They say their findings indicate that CRY1 promotes tumor progression by altering DNA repair, and could represent a new therapeutic target for prostate cancer.
“It’s been shown that circadian disruptions can affect efficacy of treatment, but also that aligning treatment with the body’s natural rhythms or giving therapy at certain times of the day can be beneficial,” said Karen E. Knudsen, PhD, executive vice president of oncology services for Jefferson Health and enterprise director of SKCC, and senior author of the study, which is published in Nature Communications. “Our findings open up a multitude of important research questions exploring the link between the circadian clock and cancer.” Knudsen and colleagues report in their studies in a paper titled, “The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair,” in which they conclude that their findings, “… nominate a new, targetable pathway for managing advanced PCa.”
Our circadian clock synchronizes our bodily processes to the natural rhythms of light and dark, and studies indicate that disrupting this clock can wreak havoc on our bodies. Research has shown that disturbance of circadian rhythms through sleep deprivation, jet lag, or shift work, for example, is linked with an increased incidence of some cancers, including prostate cancer (PCa), which is the second leading cause of cancer death for men in the U.S. “Loss of circadian control is also associated with poor efficacy of anticancer treatments and early mortality among cancer patients,” the authors noted.
Knudsen and colleagues have now linked the circadian factor CRY1—a transcription regulatory—with prostate cancer. “When we analyzed human cancer data, the circadian factor CRY1 was found to increase in late stage prostate cancers, and is strongly associated with poor outcomes,” explained Knudsen. “However, the role CRY1 in human cancers has not been explored.”
A common therapy for prostate cancer involves suppressing the male androgen hormone and/or the androgen receptor (AR), as prostate tumors require androgens to develop and progress to advanced disease. However, treatment resistance can develop to standard therapeutic approaches. “First-line therapy for patients with disseminated disease targets the androgen receptor (AR), a ligand-dependent transcription factor required for PCa development and progression,” the authors explained. “Although androgen depletion and AR-targeted therapies are initially effective, recurrent castration-resistant prostate cancer (CRPC) arises for which there is no durable cure.”
Working with collaborators in the U.S. and in Europe, the researchers’ studies using prostate tumor tissue obtained from patients showed that CRY1 is induced by the androgen receptor, which in part explains the high levels of CRY1 observed in human disease. “This was a clear indication of CRY1’s link to prostate cancer,” said study first author, Ayesha Shafi, PhD, a postdoctoral researcher in Knudsen’s lab. “As we looked further into the role of CRY1, we unexpectedly found that the circadian factor was altering the way that cancer cells repair DNA.”
Cancer treatments aim to damage the DNA in cancer cells and cause defects in repair mechanisms; eventually the cells self-destruct when the damage is severe. The researchers probed the possible role of CRY1 in DNA repair in cultured cells, animal models and tissue harvested from prostate cancer patients. They first induced DNA damage by exposing cancer cells to radiation, and found that CRY1 levels increased, indicating that it was responding to this type of damage. They also found that CRY1 directly regulated the availability of factors essential for the DNA repair process, and altered the means by which cancer cells responded to DNA damage. As the team wrote, “Critically, findings herein strongly link tumor-specific CRY1 induction with poor outcome and altered DNA repair processes … A central finding is that CRY1 regulates gene expression far beyond that associated with circadian rhythm … Combined, these studies implicate CRY1 induction (as achieved by AR signaling and/or amplification of the CRY1 locus), as an effector of disease progression.”
These findings suggested that CRY1 may offer a protective effect against damaging therapies. “The fact that CRY1 is elevated in late-stage prostate cancer may explain why androgen-targeting treatments become ineffective at those later stages,” Shafi commented. “It also tells us that if a tumor has high levels of CRY1, DNA repair targeting treatments may be less effective for them.”
Knudsen further noted, “Not only have we outlined a role for CRY1 outside of its canonical function in circadian rhythms, Shafi’s findings are the first to reveal the means by which CRY1 contributes to aggressive disease. It’s notable that the pro-tumor functions of CRY1 may be viable targets to treat prostate cancer, and this is a direction that Shafi’s future work will explore.”
The authors stated, “The present findings underscore the importance of discerning cancer promoting factors beyond canonical function by yielding critical insight into androgen-regulated CRY1 function and a novel role in DNA repair while nominating potentially impactful therapeutic targets to enhance patient outcome of this lethal disease.”
Looking ahead, the investigators plan to explore how best to target and block CRY1 and what other existing therapies may work synergistically to hinder DNA repair in prostate cancer cells. “These studies are the first to delineate the molecular framework used by CRY1 to enhance cancer progression and nominate CRY1-DNA repair pathways as a potential node for therapeutic targeting in late stage disease,” they wrote. They also plan to study more circadian rhythm genes and determine how circadian disruption may affect cancer treatment.
“It’s been shown that circadian disruptions can affect efficacy of treatment, but also that aligning treatment with the body’s natural rhythms or giving therapy at certain times of the day can be beneficial,” explained Knudsen. “Our findings open up a multitude of important research questions exploring the link between the circadian clock and cancer.”