The cutaneous circadian clock as a determinant of environmental vulnerability: Molecular pathways and chrono-pharmacological opportunities

Abstract

Circadian clocks have received consistent attention for decades due to their great potential for elucidating the mechanisms underlying psychiatric and neurodegenerative diseases. More recently, attention has been focused on molecular mechanisms contributing to other health outcomes, especially malignancies. The circadian system is essential for normal cellular homeostasis and maintenance of biological rhythms at cellular and systemic levels. Since circadian regulation has implications in a wide range of physiological functions, disrupted clocks can lead to metabolic diseases, including cancer. In addition, emerging evidence indicates that circadian regulation is critically involved in the pathogenesis of several cutaneous diseases. Solar radiation is the main cause of skin cancer as well as other skin conditions and, coincidentally, it is an important environmental time cue for human circadian rhythms. Moreover, circadian regulation of melatonin production can protect or repair solar UV-induced DNA damage, which has therapeutic prospects for skin cancer owing to endocrine and physiological functions of melatonin. Circadian mechanisms also have multidisciplinary interventions with epigenetic mechanisms in the rhythmic expression of clock genes. Considering the vulnerability of skin cells to environmental changes, skin can be a principal target of current therapeutic approaches based on circadian mechanisms. Therefore, chronotherapeutic intervention studies may yield more clinically meaningful results for curing or preventing cutaneous diseases including skin cancer. In this review, we discuss recent progress in our understanding of skin circadian mechanisms as they are challenged by environmental factors and future directions in designing strategies for chronotherapeutic applications.