New Insights Into Cancer Chronotherapies

Circadian clocks participate in the coordination of various metabolic and biological activities to maintain homeostasis. Disturbances in the circadian rhythm and cancers are closely related. Circadian clock genes are differentially expressed in many tumors, and accelerate the development and progression of tumors. In addition, tumor tissues exert varying biological activities compared to normal tissues due to resetting of altered rhythms. Thus, chronotherapeutics used for cancer treatment should exploit the timing of circadian rhythms to achieve higher efficacy and mild toxicity. Due to interpatient differences in circadian functions, our findings advocate an individualized precision approach to chronotherapy. Herein, we review the specific association between circadian clocks and cancers. In addition, we focus on chronotherapies in cancers and personalized biomarkers for the development of precision chronotherapy. The understanding of circadian clocks in cancer will provide a rationale for more effective clinical treatment of tumors.

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Circadian Rhythm: Potential Therapeutic Target for Atherosclerosis and Thrombosis

International Journal of Molecular Sciences ◽

10.3390/ijms22020676 ◽

2021 ◽

Vol 22 (2) ◽

pp. 676

Author(s):

Andy W. C. Man ◽

Huige Li ◽

Ning Xia

Keyword(s):

Circadian Rhythm ◽

Cardiovascular Diseases ◽

Circadian Rhythms ◽

Circadian Clock ◽

Therapeutic Target ◽

Environmental Changes ◽

Clock Genes ◽

Vascular System ◽

Peripheral Tissues ◽

Inflammatory Processes

Every organism has an intrinsic biological rhythm that orchestrates biological processes in adjusting to daily environmental changes. Circadian rhythms are maintained by networks of molecular clocks throughout the core and peripheral tissues, including immune cells, blood vessels, and perivascular adipose tissues. Recent findings have suggested strong correlations between the circadian clock and cardiovascular diseases. Desynchronization between the circadian rhythm and body metabolism contributes to the development of cardiovascular diseases including arteriosclerosis and thrombosis. Circadian rhythms are involved in controlling inflammatory processes and metabolisms, which can influence the pathology of arteriosclerosis and thrombosis. Circadian clock genes are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system. The circadian machinery in the vascular system may be a novel therapeutic target for the prevention and treatment of cardiovascular diseases. The research on circadian rhythms in cardiovascular diseases is still progressing. In this review, we briefly summarize recent studies on circadian rhythms and cardiovascular homeostasis, focusing on the circadian control of inflammatory processes and metabolisms. Based on the recent findings, we discuss the potential target molecules for future therapeutic strategies against cardiovascular diseases by targeting the circadian clock.

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Modulatory Effects of Circadian Rhythms in the Lung Adenocarcinoma Tumor Microenvironment

10.21203/rs.3.rs-838444/v1 ◽

2021 ◽

Author(s):

Qianzhun Huang ◽

Xiaoyang Su ◽

Ning Fang ◽

Jian Huang

Keyword(s):

Tumor Microenvironment ◽

Circadian Rhythms ◽

Lung Adenocarcinoma ◽

Circadian Clock ◽

Drug Sensitivity ◽

Molecular Mechanisms ◽

Clock Genes ◽

Functional Enrichment ◽

Expression Levels ◽

Circadian Clock Genes

Abstract Background: Dysregulated circadian dynamic balance is strongly associated with cancer development. However, biological functions of circadian rhythms in lung adenocarcinoma (LUAD) have not been elucidated. This study aimed at valuating the modulatory effects of circadian rhythms in the LUAD tumor microenvironment.Methods: Multiple open-source bioinformatics research platforms are used to comprehensively elucidate the expression level, prognosis, potential biological function, drug sensitivity, and immune microenvironment of circadian clock genes in LUAD.Results: Most circadian clock genes in LUAD are dysregulated and are strongly correlated with patient prognosis, and missense mutations at splicing sites of these genes. Besides, these genes are closely associated with some well-known cancer-related marker pathways, which are mainly involved in the inhibition of the Apoptosis, Cell cycle, and DNA Damage Response Pathway. Furthermore, functional enrichment analysis revealedthat circadian clock genes regulate transcription factor activities and circadian rhythms in LUAD tissues. As for drug sensitivity, high expression of CLOCK, CRY1, and NR1D2 as well as suppressedPER2 and CRY2 expression levels are associated with drug resistance. The expression levels of circadian clock genes in LUAD correlate with immune infiltration and are involved in the regulation of immunosuppression.Conclusions: Our multi-omics analysis provides a more comprehensive understanding of the molecular mechanisms of the circadian clock genes in LUAD and provides new insights for a more precise screening of prognostic biomarkers and immunotherapy.

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Chronic Corticosterone Disrupts the Circadian Rhythm of CRH Expression and M6a RNA Methylation in the Chicken Hypothalamus

10.21203/rs.3.rs-919584/v1 ◽

2021 ◽

Author(s):

Yang Yang ◽

Wanwan Han ◽

Aijia Zhang ◽

Mindie Zhao ◽

Wei Cong ◽

...

Keyword(s):

Circadian Rhythm ◽

Circadian Rhythms ◽

Chronic Stress ◽

Hpa Axis ◽

Clock Genes ◽

Diurnal Fluctuation ◽

Opposite Pattern ◽

Rna Methylation ◽

Diurnal Patterns ◽

M6a Rna Methylation

Abstract Corticotropin-releasing hormone (CRH), the major secretagogue of the hypothalamic-pituitary-adrenal (HPA) axis, is intricately intertwined with the clock genes to regulate the circadian rhythm of various body functions. N6-methyladenosine (m6A) RNA methylation is involved in the regulation of circadian rhythm, yet it remains unknown whether CRH expression and m6A modification oscillate with the clock genes in chicken hypothalamus and how the circadian rhythms change under chronic stress. Here, we show that chronic exposure to corticosterone (CORT) eliminated the diurnal patterns of plasma CORT and melatonin levels in the chicken. The circadian rhythms of clock genes in hippocampus, hypothalamus and pituitary are all disturbed to different extent in CORT-treated chickens. The most striking changes occur in hypothalamus in which the diurnal fluctuation of CRH mRNA is flattened, together with mRNA of other feeding-related neuropeptides. Interestingly, hypothalamic m6A level oscillates in an opposite pattern to CRH mRNA, with lowest m6A level after midnight (ZT18) corresponding to the peak of CRH mRNA before dawn (ZT22). CORT diminished the circadian rhythm of m6A methylation with significantly increased level at night. Further site-specific m6A analysis on 3’UTR of CRH mRNA indicates that higher m6A on 3’UTR of CRH mRNA coincides with lower CRH mRNA at night (ZT18 and ZT22). Our results indicate that chronic stress disrupts the circadian rhythms of CRH expression in hypothalamus, leading to dysfunction of HPA axis in the chicken. RNA m6A modification is involved in the regulation of circadian rhythms in chicken hypothalamus under both basal and chronic stress conditions.

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Abstract P160: Non-invasive Method to Assess Human Circadian Rhythms

Hypertension ◽

10.1161/hyp.68.suppl_1.p160 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Daian Chen ◽

S Justin Thomas ◽

David A Calhoun ◽

David M Pollock ◽

Jennifer S Pollock

Keyword(s):

Circadian Rhythm ◽

Circadian Rhythms ◽

Salivary Cortisol ◽

Metabolic Diseases ◽

Clock Genes ◽

Light Exposure ◽

Rna Isolation ◽

Buccal Cells ◽

Non Invasive ◽

Salivary Melatonin

Circadian rhythms are controlled by an endogenous time-keeping system oscillating approximately on a 24-h cycle under constant conditions. These rhythms depend on a network of interacting genes and proteins, including transcriptional activators such as CLOCK, NPAS2, and ARNTL (BMAL1), which induce transcription of the clock genes Period ( Per1 , Per2 , and Per3 ) and Cryptochrome ( Cry1 and Cry2 ). Human salivary cortisol and melatonin follow a clear circadian rhythm as well. Disruption of the circadian rhythm and sleep-wake cycles are considered risk factors for a variety of health problems, especially hypertension and other cardiovascular and metabolic diseases. Here we put together practical methods for assessing circadian rhythms in adult subjects conducted by each individual. This method is non-invasive, inexpensive and provides a predictive profile of an individual’s circadian rhythm related to clock-controlled gene expression in buccal cells, salivary cortisol, salivary melatonin, and subject’s activity or sleep. Subjects are instructed on how to obtain buccal cells using swabs (Whatman OmniSwab) from the inside of their cheeks and collect saliva using salivettes (Sarstedt) every 4 hours starting at 6am, for 2 consecutive days. Subjects also wear actigraphy watches (Phillips Respironics) during the 2 days, to record their activity, light exposure and estimates of sleep times. To monitor adherence to correct time point collections, each subject is given an electronic vial called eCAP (Information Mediary Corp) that records the exact time the container is opened to place samples once collected. We demonstrate feasibility to extract up to 150ng/μl of RNA (Ambion RNAqueous-Micro Total RNA Isolation Kit) from buccal cells swabs. Salivary melatonin and cortisol are measured by radioimmunoassay (Buhlmann Lab) with melatonin peak levels ranging from 14 to 23 pg/ml and cortisol peak levels ranging from 10 to 24 ng/ml. We suggest that buccal cell expression of clock-controlled genes, salivary melatonin, salivary cortisol, and actigraphy data are valuable in providing reliable assessment of human circadian rhythm profiles under a variety of conditions.

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Abolished Daily Expression Patterns of SIRT1, SIRT2, and SIRT5 in Human Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4613.4613 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4613-4613

Author(s):

Ming-Yu Yang ◽

Pai-Mei Lin ◽

Jui-Feng Hsu ◽

Wen-Chi Yang ◽

Yi-Chang Liu ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Circadian Rhythms ◽

Circadian Clock ◽

Myeloid Leukemia ◽

Clock Genes ◽

Expression Patterns ◽

Healthy Individuals ◽

Daily Pattern ◽

Genes Expression ◽

Circadian Clock Genes

Abstract Abstract 4613 Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Chronobiological issues of sleep and circadian rhythms

European Psychiatry ◽

10.1016/s0924-9338(11)73836-6 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 2133-2133

Author(s):

G. Hajak

Keyword(s):

Circadian Rhythm ◽

Clock Genes ◽

Phase Relationship ◽

Temporal Organization ◽

Stable Phase ◽

Delayed Sleep Phase Syndrome ◽

Circadian Rhythm Sleep Disorders ◽

Delayed Sleep Phase ◽

Circadian Clock Genes ◽

Delayed Sleep

Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with data that deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders.At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Usually our sleep/wake cycle, temperature and melatonin rhythms are internally synchronized with a stable phase relationship. When there is a desynchrony between the sleep/wake cycle and circadian rhythm, sleep disorders such as advanced and delayed sleep phase syndrome can arise as well as transient chronobiologic disturbances, for example from jet lag and shift work.Increasing evidence suggests that disrupted temporal organization of biological functions impairs behaviour, cognition, affect, and emotion. Furthermore, disruption of circadian clock genes impairs the sleep-wake cycle and social rhythms, which may be implicated in particular in mental disorders. An increasing number of journal publications point to a crucial role of circadian rhythm dysregulations in particular for affective disorders, which should e addressed specifically in modern psychiatry.

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Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances

Biochemical Pharmacology ◽

10.1016/j.bcp.2008.01.011 ◽

2008 ◽

Vol 75 (8) ◽

pp. 1616-1622 ◽

Cited By ~ 20

Author(s):

Hideyuki Terazono ◽

Ahmed Hamdan ◽

Naoya Matsunaga ◽

Naoto Hayasaka ◽

Hiroaki Kaji ◽

...

Keyword(s):

Circadian Rhythm ◽

Circadian Clock ◽

Clock Genes ◽

Rhythmic Expression ◽

Circadian Clock Genes

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Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

10.1101/2020.10.09.333732 ◽

2020 ◽

Author(s):

Yangbo Xiao ◽

Ye Yuan ◽

Mariana Jimenez ◽

Neeraj Soni ◽

Swathi Yadlapalli

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Nuclear Envelope ◽

Circadian Clock ◽

Clock Genes ◽

Circadian Clocks ◽

Spatiotemporal Organization ◽

Clock Proteins ◽

Expression Behavior ◽

Clock Protein

ABSTRACTCircadian clocks regulate ∼24 hour oscillations in gene expression, behavior, and physiology. While the molecular and neural mechanisms of circadian rhythms are well characterized, how cellular organization of clock components controls circadian clock regulation remains poorly understood. Here, we elucidate how clock proteins regulate circadian rhythms by controlling the spatiotemporal organization of clock genes. Using high-resolution live imaging techniques we demonstrate that Drosophila clock proteins are concentrated in a few discrete foci and are organized at the nuclear envelope; these results are in contrast to longstanding expectations that clock proteins are diffusely distributed in the nucleus. We also show that clock protein foci are highly dynamic and change in number, size, and localization over the circadian cycle. Further, we demonstrate that clock genes are positioned at the nuclear periphery by the clock proteins precisely during the circadian repression phase, suggesting that subnuclear localization of clock genes plays an important role in the control of rhythmic gene expression. Finally, we show that Lamin B receptor, a nuclear envelope protein, is required for peripheral localization of clock protein foci and clock genes and for normal circadian rhythms. These results reveal that clock proteins form dynamic nuclear foci and play a hitherto unexpected role in the subnuclear reorganization of clock genes to control circadian rhythms, identifying a novel mechanism of circadian regulation. Our results further suggest a new role for clock protein foci in the clustering of clock-regulated genes during the repression phase to control gene co-regulation and circadian rhythms.SIGNIFICANCEAlmost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate ∼24-hour oscillations in gene expression, behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of clock proteins and clock genes and its critical role in circadian clock function. We show, in contrast to current expectations, that clock proteins are concentrated in a few discrete, dynamic nuclear foci at the nuclear envelope during the repression phase. Further, we uncovered several unexpected features of clock protein foci, including their role in positioning the clock genes at the nuclear envelope precisely during the repression phase to enable circadian rhythms. These studies provide fundamental new insights into the cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian clocks.

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