Circadian clock and cancer: From a viewpoint of cellular differentiation

Abstract

Abbreviations & Acronyms AML = acute myeloid leukemia ccg = clock-controlled gene DNMT1 = DNA methyltransferase 1 E19 = embryonic day 19 ES = embryonic stem iPS = induced pluripotent stem MEF = mouse embryonic fibroblast MRT = malignant rhabdoid tumor OSKM = Oct3/4, Sox2, Klf4 and c-Myc Per2 Luc = Per2::Luciferase SCN = suprachiasmatic nucleus SMG = submandibular gland TTFL = transcriptionaltranslational feedback loop UPR = unfolded protein response Correspondence: KazuhiroAbstract: The circadian clock controls and adapts diverse physiological and behavioral processes according to Earth's 24-h cycle of environmental changes. The master pacemaker of the mammalian circadian clock resides in the hypothalamic suprachiasmatic nucleus, but almost all cells throughout the body show circadian oscillations in gene expression patterns and associated functions. Recent studies have shown that the circadian clock gradually develops during embryogenesis. Embryonic stem cells and induced pluripotent stem cells do not show circadian oscillations of gene expression, but gradually develop circadian clock oscillation during differentiation; thus, the developmental program of circadian clock emergence appears closely associated with cellular differentiation. Like embryonic stem cells, certain cancer cell types also lack the circadian clock. Given this similarity between embryonic stem cells and cancer cells, interest is growing in the contributions of circadian clock dysfunction to dedifferentiation and cancer development. In this review, we summarize recent advances in our understanding of circadian clock emergence during ontogenesis, and discuss possible associations with cellular differentiation and carcinogenesis. Considering the multiple physiological functions of circadian rhythms, circadian abnormalities might contribute to a host of diseases, including cancer. Insights on circadian function could lead to the identification of biomarkers for cancer diagnosis and prognosis, as well as novel targets for treatment. Hierarchical organization of the mammalian circadian clockMost organisms have evolved an intrinsic circadian clock to adapt physiological functions to the planet's 24-h environmental cycles. In mammals, the circadian clock controls such physiological and behavioral functions as sleep-wake cycles, metabolism, hormonal secretion, body temperature, immune responses and neuronal functions. 1,2 The master pacemaker of the mammalian circadian clock resides in the SCN of the hypothalamus. A subset of SCN neurons receive a clock-resetting light signal from the retinohypothalamic tract and communicate with other SCN cells to maintain robust circadian oscillations of neuronal activity. These neuronal oscillations in turn synchronize other peripheral oscillators throughout the body through neuronal and hormonal signaling pathways. 3,4 At the cellular and molecular levels, the circadian clock is comprised of a set of core clock genes functionally organized into TTFLs that generate cell-autonomous circadian oscillations in gene ex...

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