Circadian Rhythm Disruption as a Contributor to Racial Disparities in Prostate Cancer

Abstract

In the United States, African American (AA) men have a 2.4 times higher mortality rate due to prostate cancer than White men. The multifactorial causes of the racial disparities in prostate cancer involve various social determinants of health, socioeconomic status, and access to healthcare. However, emerging evidence also suggests that circadian rhythm disruption (CRD) contributes to prostate cancer, and AA men may be more susceptible to developing CRDs. Circadian rhythms play a significant role in metabolism, hormone secretion, and sleep/wake cycles. Disruption in these circadian rhythms can be caused by airplane travel/jetlag, night shift work, exposure to light, and neighborhood noise levels, which can contribute to sleep disorders and chronic conditions such as obesity, diabetes, cardiovascular disease, and depression. The drivers of the racial disparities in CRD include night shift work, racial discrimination, elevated stress, and residing in poor neighborhoods characterized by high noise pollution. Given the increased vulnerability of AA men to CRDs, and the role that CRDs play in prostate cancer, elucidating the clock-related prostate cancer pathways and their behavior and environmental covariates may be critical to better understanding and reducing the racial disparities in prostate cancer.

Keywords: artificial light at night; circadian genes; jet lag; melatonin; night shift work; obesity; prostate cancer; racial disparities; stress; treatment resistance.

Figure 1

Schematic Representation of the Circadian Clock Transcriptional–Translational Feedback Loops. The main feedback loop is comprised of activator proteins Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), and two repressor proteins, Period (PER) and Cryptochrome (CRY). BMAL1 and CLOCK heterodimerize and bind to the E-box, which activates the transcription of CRY (1-2), PER (1-3), RORα, REV-ERBα, and Clock transcription factors (TFs). The primary negative feedback occurs when CRY and PER accumulate and dimerize in the cytoplasm and translocate to the nucleus to inhibit the BMAL1: CLOCK. In the secondary feedback loop, RORα and REV-ERBα activate and inhibit the transcription of BMAL1.

Figure 2

Overlapping Risk Factors for Circadian Rhythm Disruptions and Racial Disparities in Circadian health regarding Prostate Cancer Risk. The right-hand side of the Venn diagram describes environmental, structural, and health-related factors that contribute to the racial disparities in circadian health. Specifically, these factors disproportionately affect the AA population compared to other racial/ethnic groups. The left-hand side outlines the causes of circadian rhythm disruptions. The arrows inside the Venn diagram indicate that there is a bidirectional relationship between the causes of CRDs and social determinants of health. Taken together, the top half of the model illustrates how the African American population is disproportionately at risk for developing CRDs. The bottom half of the model focuses on the downstream effects of circadian rhythm disruption on prostate cancer, both in incidence and aggressiveness.