**Author details**

*Oncogenes and Carcinogenesis*

cell cycle adjustments.

to be tumor-prone [9].

**Acknowledgements**

basis of cancer chronotherapy.

**10. Conclusion**

[69, 70]. In this scenario, increasing levels of oxygen-free radicals during the daytime may be a decisive factor in relegating the anabolic processes of mitosis, growth, and consolidation to the dark hours. Thus, it is reasonable that cellular signaling cascade mediated by ROS is utilized in the regulation of the circadian clocks and that common regulatory pathways mediate both cellular responses to photooxidative stress

In addition to the photooxidative stress derived from sunlight, the UV component of it is major source of harm to organisms [51, 52]. In zebrafish, the light induces expression of PHRs which repair UV-damaged DNA in a light-dependent manner (**Figure 2**) [49, 71]. Importantly, this light induction of *DNA Phr* expression appears to be mediated by photooxidative stress [68, 72]. These observations are consistent with the idea that photooxidative stress may be utilized as a signal to activate DNA repair enzymes that can protect the organism's DNA from UV-induced damage. The fact that ROS, a well-known inducer of oxidative stress, can activate *zCry1a* transcription in zebrafish cells [66], together with the finding that *zCry1a* and *DNA Phr* are governed by shared light-induced signaling pathways [49], strongly suggests that, at least in zebrafish, the light entrainment of the circadian clock reflects a long-standing cellular response to photooxidative stress (**Figure 2**). The zCRY1a protein interacts directly with the CLOCK (NPAS2):BMAL complexes and regulates its transcriptional capacity [67, 73]. The complexes regulate a variety of key genes involved in cellular stress responses, DNA repair, and cell cycle regulation [14, 74]. Thus, the circadian clock protein zCRY1a may be the key integrator of oxidative stress that controls the core circadian machinery to regulate the transcription of genes responsible for DDR and

Many studies have identified a link between the circadian clock and tumorigenesis [8, 12]. The core of the circadian clock mechanism is the cell-autonomous and self-sustained transcriptional machinery called the cellular clock. Importantly, the cellular clocks have been reported to regulate transcription of tumor suppressors and cell cycle regulators [6, 12]. In addition, circadian proteins appear to play roles in cell cycle control, acting as tumor suppressors [9]. For example, it has been hypothesized that a core circadian regulator, CLOCK, directly interacts with key checkpoint proteins, leading to the acetylation of these proteins and thereby modulating their activities. In support of this idea, *Clock* mutant mice have been reported

Cancer chronotherapy relies on the asynchrony that exists in cell proliferation and drug sensitivities between normal and malignant cells [8, 12]. The administration of cancer therapy based on circadian timing has had encouraging results, but still lacks a strong mechanistic foundation. Thus, identification of detailed molecular links between the circadian clocks and tumorigenesis will provide the functional

This work was supported in part by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research [16K08521 and 18KT0068

(J.H.)]. This work was also supported by grant from Komatsu University

and the light-dependent regulation of the circadian clocks (**Figure 2**).

**20**

(J.I. and J.H.).

Yoshimi Okamoto-Uchida1 , Junko Izawa<sup>2</sup> and Jun Hirayama2 \*

1 Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan

2 Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University, Ishikawa, Japan

\*Address all correspondence to: jun.hirayama@komatsu-u.ac.jp

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
