Roles of the circadian clock- and sex-related mechanisms in melanomagenesis and therapeutic applications

Panshak Dakup

The circadian clock is a coordinated network that generates rhythms spanning from molecules to physiology. This network aligns with the 24-hour period of a day and is maintained by an organism’s response to daily environmental cues. Rhythmic expression of core clock genes generates oscillatory expression patterns of target genes/proteins in a tissue-specific manner, driving biological activities. Consequently, balance in the cycling of DNA repair and immune proteins is essential to maintain a healthy state. Disruption of circadian homeostasis has been linked with non-melanoma and melanoma skin carcinogenesis. Recently, circadian disruption by shift work was classified as a ‘Group 2A’ carcinogen by the International Agency for Research on Cancer, indicating ‘probably carcinogenic to humans.’ Additionally, ultraviolet (UV) radiation and biological sex are predisposing risk factors for melanoma. However, the molecular mechanisms explaining melanomagenesis in the context of shift work and sex disparity have not been investigated for the prevention and treatment of the disease. For circadian clock-related studies, we utilized cellular and mouse models under control and disrupted (rotating shift and/or Period1/2 deficient) circadian conditions, and for sex-related studies, we used male and female mice. We report that nucleotide excision repair (NER) of UVB radiation-induced photoproducts was transcriptionally regulated by the circadian clock through Atr-mediated checkpoint response and the availability of chromatin-bound repair proteins. This clock-regulated response to UVB prevented mutagenesis of UVB exposed cells. During melanoma progression, we observed slower tumor growth in female mice compared to male mice. This observation was associated with higher immune response of CD4+ and CD8+ T cells in female mice. Regarding therapeutic applications, the circadian control of NER, through rate limiting factor Xpa, resulted in less toxicity with evening compared to morning administration of cisplatin, both in melanoma mouse models and human blood samples. Likewise, radiation therapy applied to mice in the evening showed circadian clock protection of the skin and heart via Bmal1. In summary, the circadian control of cellular response mechanisms against genotoxic stress plays a protective role in preventing carcinogenesis and reducing toxicity of certain therapeutic agents. The circadian network is potentially a useful tool for developing personalized medicine strategies.

Roles of the circadian clock- and sex-related mechanisms in melanomagenesis and therapeutic applications

Files and links (1)

Abstract

Metrics

Details