Clock genes and cancer development in particular in endocrine tissues

Abstract

Circadian rhythms at a central and peripheral level are operated by transcriptional/translational feedback loops involving a set of genes called ‘clock genes’ that have been implicated in the development of several diseases, including malignancies. Dysregulation of the Clock system can influence cancer susceptibility by regulating DNA damage and repair mechanisms, as well as apoptosis. A number of oncogenic pathways can be dysregulated via clock genes’ epigenetic alterations, including hypermethylation of clock genes’ promoters or variants of clock genes. Clock gene disruption has been studied in breast, lung and prostate cancer, and haematological malignancies. However, it is still not entirely clear whether clock gene disruption is the cause or the consequence of tumourigenesis and data in endocrine neoplasms are scarce. Recent findings suggest that clock genes are implicated in benign and malignant adrenocortical neoplasias. They have been also associated with follicular and papillary thyroid carcinomas and parathyroid adenomas, as well as pituitary adenomas and craniopharyngiomas. Dysregulation of clock genes is also encountered in ovarian and testicular tumours and may also be related with their susceptibility to chemotherapeutic agents. The most common clock genes that are implicated in endocrine neoplasms are PER1, CRY1; in most cases their expression is downregulated in tumoural compared to normal tissues. Although there is still a lot to be done for the better understanding of the role of clock genes in endocrine tumourigenenesis, existing evidence could guide research and help identify novel therapeutic targets aiming mainly at the peripheral components of the clock gene system.

Transcription Factor Profiling to Predict Recurrence-Free Survival in Breast Cancer: Development and Validation of a Nomogram to Optimize Clinical Management

“…Moreover, PLAGL1 (ZAC1/LOT1) expression has been shown to be associated with disease progression and unfavorable prognosis in clear cell renal cell carcinoma (Godlewski et al, 2016). Furthermore, TBX2 acts as a neuroblastoma core regulatory circuitry component that promotes MYCN/FOXM1-mediated reactivation of DREAM targets (Decaesteker et al, 2018), while CLOCK genes are closely associated with cancer development, particularly in endocrine tissues (Angelousi et al, 2019).…”

Thyroid Cancer and Circadian Clock Disruption

“…In support of the existence of a thyroid clock, circadian oscillations for core clock genes have been demonstrated in rats as well as in in vitro synchronized human primary thyrocytes, which present a circadian period length of about 27 h [ 8 , 228 ]. Different studies, although sometimes with conflicting results, have demonstrated a possible relationship between circadian clockwork and thyroid tumorigenesis [ 5 , 6 , 7 , 8 , 9 , 10 ].…”

“…Recently a relationship between the circadian clock machinery function and TC has been proposed [ 5 , 6 , 7 , 8 , 9 , 10 ]. During evolution, organisms have developed biological clocks to better adapt to various rhythmic events such as daily and seasonal fluctuations.…”

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

“…REV-ERBs bind to the same RORE DNA response elements as RORs in the form of both a monomer (an AGG TCA half site with a 5 AT-rich extension) or a homodimer (RevDR2, RGG TCA NN RGG TCA) [78]. This interactive positive and negative regulation on RORE transactivation by RORs and REV-ERBs shapes the oscillating expression of BMAL1, while REV-ERB expression is negatively regulated by PER/CRY proteins and positively regulated by CLOCK/BMAL1, complicating the feedback loop of the circadian clock system [79]. REV-ERBα null mice display altered circadian rhythms characterized by increased CLOCK/BMAL1 expression and shorter period lengths when compared to wild-type mice [78].…”