Fig. 2

The circadian clock system is a complex transcriptional–translational autoregulatory network with activating and inhibitory components. Brain Muscle Arnt-Like protein-1 (BMAL1), the major component of the endogenous clock, heterodimerizes with Circadian Locomotor receptor Cycles Output Kaput (CLOCK) or Neuronal PAS domain protein 2 (NPAS2) to generate active transcription factor heterodimers. Binding of these dimers to the Enhancer-box (E-box) elements of their target genes leads to the expression of genes that encode the transcription repressors Cryptochrome (CRY1 and CRY2) and Period (PER1, PER2, PER3) [30, 31, 33, 34]. CRY and PER complexes inhibit CLOCK/BMAL1 transcriptional activity. CLOCK/BMAL1 dimers also drive the transcription of the nuclear receptors REV-ERBα and retinoid-related orphan receptor α (RORα) that represses and activates BMAL1 transcription, respectively [35]. Clock genes regulate the expression of clock-controlled regulators and also of genes that can be implicated in tumorigenesis. Therefore, their dysregulation might affect several cancer-related processes such as cell-cycle control, apoptosis, metabolic regulation, and DNA damage response. Circadian rhythm disruption might play a more critical role in tumor formation and progression than genetic factors [36]. Aberrant expression of circadian genes has been observed in different human cancers: head and neck squamous cell carcinoma, leukemia, ovarian, oral, and prostate cancer [37,38,39,40,41]