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Circadian clock role in prostate cancer

Researchers have explored the circadian clock and found an unexpected role for the clock gene CRY-1 in prostate cancer progression.

Prostate cancer

Prostate cancer is the second leading cause of cancer death in men in the US. The first-line therapy for patients with disseminated disease targets the androgen receptor (AR). Although initially effective, these targeted therapies often lead to recurrent castration-resistant prostate cancer (CRPC), where there is no durable cure. CRPC remains largely AR-dependent due to aberrant reactivation of AR through multiple different mechanisms. Therefore, there is an urgent need to develop new strategies to enhance and/or act in concert with AR-targeted therapy. Recent findings have highlighted the potential of leveraging AR-dependent DNA repair. For example, a recent clinical study revealed that tumours with pathogenic DNA repair factor alterations responded more favourably than those with no detectable DNA repair alterations to androgen depleting strategies.

Role of the circadian clock

In this study, published in Nature Communications, from analyses of advanced prostate cancer, researchers unexpectedly identified CRY1 as a tumour specific, AR-mediated, critical effector of DNA repair. CRY1 is a transcriptional coregulator associated with the circadian clock. Disruption in circadian rhythm, such as jet lag, shift work, sleep disruption and suppression of melatonin, can increase risk of prostate, breast and colon cancers. Loss of circadian control is also associated with poor efficacy of anticancer treatment and early mortality.

The team found that CRY1 expression was associated with poor outcomes in prostate cancer patients. They found that CRY-1 was induced by the AR in prostate tumour tissue obtained from patients. This explains, at least in part, the high levels of CRY-1 found in human disease. Functional studies and mapping of the CRY1 cistrome and transcriptome revealed that CRY1 regulates DNA repair and the G2/M transition. DNA damage appeared to stabilise CRY1 in cancer, which was critical for efficient DNA repair. The findings suggest that CRY-1 may offer a protective effect against damaging therapies.

Dr Shafi Ayesha, first author, stated:

“The fact that CRY-1 is elevated in late-stage prostate cancer may explain why androgen-targeting treatments become ineffective at those later stages.

It also tells us that if a tumour has high levels of CRY-1, DNA repair targeting treatments may be less effective for them.”

The team are now looking to explore how best to target and block CRY-1 and what other existing therapies may work synergistically to hinder DNA repair in prostate cancer cells.

Image credit: Photo by National Cancer Institute on Unsplash

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Cancer / Circadian clocks / Prostate Cancer