Role of Clock Genes and Circadian Rhythm in Renal Cell Carcinoma: Recent Evidence and Therapeutic Consequences

Circadian rhythms are physical, mental, and behavioral changes that follow a 24-h cycle. These natural processes primarily respond to light and dark, and affect most living things, including animals, plants, and microbes. Circadian rhythm is also involved in the regulation of cellular differentiation and physiology as well as in the modulation of the immune system. Some genes controlling circadian rhythm may be implicated in the occurrence of common malignant cancers, including renal cell carcinoma. Recent studies showed that time-of-day infusion directly conditions the efficacy of immunotherapy in patients with cancer. Drugs targeting the circadian clock have been identified and their role in the era of immunotherapy should be investigated. In this review, we illustrate the role of clock genes in kidney cancer onset, progression and prognosis, and the potential therapeutic consequences of this emerging evidence. Circadian rhythm regulates cellular differentiation and physiology and shapes the immune response. Altered expression of clock genes might lead to the onset of common malignant cancers, including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock genes PER1-3, CRY2, CLOCK, NR1D2 and ROR alpha are overexpressed in RCC tissues and correlate with patients' prognosis. The expression of clock genes could finely tune transcription factor activity in RCC and is associated with the extent of immune cell infiltration. The clock system interacts with hypoxia-induced factor-1 alpha (HIF-1 alpha) and regulates the circadian oscillation of mammalian target of rapamycin (mTOR) activity thereby conditioning the antitumor effect of mTOR inhibitors. The stimulation of natural killer (NK) cell activity exerted by the administration of interferon-alpha, a cornerstone of the first era of immunotherapy for RCC, relevantly varies according to circadian dosing time. Recent evidence demonstrated that time-of-day infusion directly affects the efficacy of immune checkpoint inhibitors in cancer patients. Compounds targeting the circadian clock have been identified and their role in the era of immunotherapy deserves to be further investigated. In this review, we aimed at addressing the impact of clock genes on the natural history of kidney cancer and their potential therapeutic implications.