Abstract A048: The importance of time: Circadian rhythm disruption and prostate cancer

Abstract

Abstract Circadian rhythms are evolutionarily created cycles programmed to integrate human behavior, physiology, and metabolism with the surrounding environment. The core clock machinery is composed of an autoregulatory network. The positive components of the loop are CLOCK and BMAL transcription factors, which heterodimerize to regulate expression of key circadian genes through E-box elements. CLOCK/BMAL regulate expression of cryptochrome (CRY1 and CRY2) and period (PER1, PER2, and PER3) genes, which are the negative components of the circadian loop. CRYs and PERs repress CLOCK/BMAL activity, thus conferring daily rhythmicity of cellular, metabolic, and physiological functions for homeostatic maintenance. Disruption to these rhythms, via nighttime light exposure or other forms of desynchronization, has been linked to poor health outcomes. Specifically, circadian disruption is designated as a probable carcinogen by the World Health Organization. Subsequent epidemiology research identified pilots and other shift workers have an increased risk of prostate cancer (PCa). Additional genomic studies identified multiple core clock genes (CCGs) with associated upregulation and/or downregulation in prostatic tumor tissues compared to benign samples. CCGs have also been found to impact several key oncogenic pathways including cell cycle control, apoptosis, DNA repair, and metabolic regulation. In order to further clarify the risk of an altered circadian genome, we analyzed multiple publicly available human PCa datasets to identify clinical correlates in both primary and metastatic disease. Intriguingly, we found genomic alterations in circadian rhythm were associated with increased Gleason score, cancer staging, and positive node status in primary disease. Furthermore, within a subset of patients with castrate-resistant prostate cancer (CRPC), those with concurrent altered CCGs had a decreased survival compared to patients without altered CCGs. This data further emphasizes the importance of circadian rhythm consideration in the context of malignancy and preventative medicine. With so many unknown questions and a high potential to identify subtypes of tumors with altered CCGs and aggressive disease, future studies are needed to improve therapeutic efficacy. Analysis of circadian genomic alterations with subsequent comparison of demographics including ethnicity, occupation, and sleep habits would expand the understanding of everyday variables on circadian disruption. Additionally, the comparison of short-term versus long-term circadian synchronizations should be analyzed to identify higher-risk populations. Lastly, the long-term goal should be to discover potential circadian targeted treatments or to identify ways of involvement of circadian rhythmicity in cancer treatment, including chronotherapy (i.e., time of day of treatment) to optimize the impact of cancer therapeutics to enhance patient outcome. Citation Format: Sierra T. Pence, Ayesha A. Shafi. The importance of time: Circadian rhythm disruption and prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A048.