scholarly journals Evidence for widespread dysregulation of circadian clock progression in human cancer

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4327 ◽  
Author(s):  
Jarrod Shilts ◽  
Guanhua Chen ◽  
Jacob J. Hughey
Keyword(s):  
Circadian Clock ◽  
Clock Gene ◽  
Clock Genes ◽  
Human Cancer ◽  
Human Tumor ◽  
Time Of Day ◽  
Large Set ◽  
Healthy Human ◽  
Promote Tumor Growth

The ubiquitous daily rhythms in mammalian physiology are guided by progression of the circadian clock. In mice, systemic disruption of the clock can promote tumor growth. In vitro, multiple oncogenes can disrupt the clock. However, due to the difficulties of studying circadian rhythms in solid tissues in humans, whether the clock is disrupted within human tumors has remained unknown. We sought to determine the state of the circadian clock in human cancer using publicly available transcriptome data. We developed a method, called the clock correlation distance (CCD), to infer circadian clock progression in a group of samples based on the co-expression of 12 clock genes. Our method can be applied to modestly sized datasets in which samples are not labeled with time of day and coverage of the circadian cycle is incomplete. We used the method to define a signature of clock gene co-expression in healthy mouse organs, then validated the signature in healthy human tissues. By then comparing human tumor and non-tumor samples from twenty datasets of a range of cancer types, we discovered that clock gene co-expression in tumors is consistently perturbed. Subsequent analysis of data from clock gene knockouts in mice suggested that perturbed clock gene co-expression in human cancer is not caused solely by the inactivation of clock genes. Furthermore, focusing on lung cancer, we found that human lung tumors showed systematic changes in expression in a large set of genes previously inferred to be rhythmic in healthy lung. Our findings suggest that clock progression is dysregulated in many solid human cancers and that this dysregulation could have broad effects on circadian physiology within tumors. In addition, our approach opens the door to using publicly available data to infer circadian clock progression in a multitude of human phenotypes.

scholarly journals Widespread dysregulation of the circadian clock in human cancer

2017 ◽  
Author(s):  
Jarrod Shilts ◽  
Guanhua Chen ◽  
Jacob J. Hughey
Keyword(s):  
Circadian Clock ◽  
Clock Gene ◽  
Human Lung ◽  
Human Cancer ◽  
Human Tumor ◽  
Time Of Day ◽  
Human Lung Cancer ◽  
Large Set ◽  
Transcriptome Data ◽  
Healthy Human

AbstractThe mammalian circadian clock is a critical regulator of metabolism and cell division. Although multiple lines of evidence indicate that systemic disruption of the circadian clock can promote cancer, whether the clock is disrupted in primary human tumors is unknown. Here we used transcriptome data from mice to define a signature of the mammalian circadian clock based on the co-expression of 12 genes that form the core clock or are directly controlled by the clock. Our approach can be applied to samples that are not labeled with time of day and were not acquired over the entire circadian (24-h) cycle. We validated the clock signature in transcriptome data from healthy human tissues, then developed a metric we call the delta clock correlation distance (ΔCCD) to describe the extent to which the signature is perturbed in samples from one condition relative to another. We calculated the ΔCCD comparing human tumor and non-tumor samples from The Cancer Genome Atlas and eight independent datasets, discovering widespread dysregulation of clock gene co-expression in tumor samples. Subsequent analysis of data from clock gene knockouts in mice suggested that clock dysregulation in human cancer is not caused solely by loss of activity of clock genes. Furthermore, by analyzing a large set of genes previously inferred to be rhythmic in healthy human lung, we found that dysregulation of the clock in human lung cancer is accompanied by dysregulation of broader patterns of circadian co-expression. Our findings suggest that clock dysregulation is a common means by which human cancers achieve unrestrained growth and division, and that restoring clock function could be a viable therapeutic strategy in multiple cancer types. In addition, our approach opens the door to using publicly available transcriptome data to quantify clock disruption in a multitude of human phenotypes. Our method is available as a web application at https://hugheylab.shinyapps.io/deltaccd.

scholarly journals Cancer clocks in tumourigenesis: the p53 pathway and beyond

2021 ◽  
Vol 28 (4) ◽  
pp. R95-R110
Author(s):  
Ewan M Stephenson ◽  
Laura E J Usselmann ◽  
Vinay Tergaonkar ◽  
David M Virshup ◽  
Robert Dallmann
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Cancer Biology ◽  
Cell Cycle Progression ◽  
Clock Genes ◽  
Human Cancer ◽  
Epidemiologic Studies ◽  
Current Evidence

Circadian rhythms regulate a vast array of physiological and cellular processes, as well as the hormonal milieu, to keep our cells synchronised to the light–darkness cycle. Epidemiologic studies have implicated circadian disruption in the development of breast and other cancers, and numerous clock genes are dysregulated in human tumours. Here we review the evidence that circadian rhythms, when altered at the molecular level, influence cancer growth. We also note some common pitfalls in circadian-cancer research and how they might be avoided to maximise comparable results and minimise misleading data. Studies of circadian gene mutant mice, and human cancer models in vitro and in vivo, demonstrate that clock genes can impact tumourigenesis. Clock genes influence important cancer-related pathways, ranging from p53-mediated apoptosis to cell cycle progression. Confusingly, clock dysfunction can be both pro- or anti-tumourigenic in a model and cell type-specific manner. Due to this duality, there is no canonical mechanism for clock interaction with tumourigenic pathways. To understand the role of the circadian clock in patients’ tumours requires analysis of the molecular clock status compared to healthy tissue. Novel mathematical approaches are under development, but this remains largely aspirational, and is hampered by a lack of temporal information in publicly available datasets. Current evidence broadly supports the notion that the circadian clock is important for cancer biology. More work is necessary to develop an overarching model of this connection. Future studies would do well to analyse the clock network in addition to alterations in single clock genes.

scholarly journals Cell type resolved co-expression networks of core clock genes in brain development

2021 ◽  
Author(s):  
Surbhi Sharma ◽  
Asgar Hussain Ansari ◽  
Soundhar Ramasamy
Keyword(s):  
Circadian Clock ◽  
Single Cell ◽  
Radial Glia ◽  
Clock Genes ◽  
Neuronal Cell ◽  
Cell Types ◽  
Developing Brain ◽  
Knock Out

AbstractThe circadian clock regulates vital cellular processes by adjusting the physiology of the organism to daily changes in the environment. Rhythmic transcription of core Clock Genes (CGs) and their targets regulate these processes at the cellular level. Circadian clock disruption has been observed in people with neurodegenerative disorders like Alzheimer’s and Parkinson’s. Also, ablation of CGs during development has been shown to affect neurogenesis in both in vivo and in vitro models. Previous studies on the function of CGs in the brain have used knock-out models of a few CGs. However, a complete catalog of CGs in different cell types of the developing brain is not available and it is also tedious to obtain. Recent advancements in single-cell RNA sequencing (scRNA-seq) has revealed novel cell types and elusive dynamic cell states of the developing brain. In this study by using publicly available single-cell transcriptome datasets we systematically explored CGs-coexpressing networks (CGs-CNs) during embryonic and adult neurogenesis. Our meta-analysis reveals CGs-CNs in human embryonic radial glia, neurons and also in lesser studied non-neuronal cell types of the developing brain.

CORTISOL CIRCADIAN RHYTHM AND INSULIN RESISTANCE IN MUSCLE: EFFECT OF DOSING AND TIMING OF HYDROCORTISONE EXPOSURE ON INSULIN SENSITIVITY IN SYNCHRONIZED MUSCLE CELLS.

2020 ◽  
Author(s):  
Mariarosaria Negri ◽  
Claudia Pivonello ◽  
Chiara Simeoli ◽  
Gilda Di Gennaro ◽  
Mary Anna Venneri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Circadian Rhythm ◽  
Insulin Sensitivity ◽  
Circadian Clock ◽  
Insulin Signaling ◽  
Clock Genes ◽  
Muscle Cells ◽  
C2c12 Cells ◽  
Circadian Expression

Introduction/Aim: Circadian rhythm disruption is emerging as a risk factor for metabolic disorders and particularly, alterations in clock genes circadian expression have been shown to influence insulin sensitivity. Recently, the reciprocal interplay between the circadian clock machinery and HPA axis has been largely demonstrated: the circadian clock may control the physiological circadian endogenous glucocorticoids secretion and action; glucocorticoids, in turn, are potent regulator of the circadian clock and their inappropriate replacement has been associated with metabolic impairment. The aim of the current study was to investigate in vitro the interaction between the timing-of-the-day exposure to different hydrocortisone (HC) concentrations on muscle insulin sensitivity. Methods: Serum-shock synchronized mouse skeletal muscle C2C12 cells were exposed to different HC concentrations recapitulating the circulating daily physiological cortisol profile (standard cortisol profile), the circulating daily cortisol profile that reached in adrenal insufficient (AI) patients treated with once-daily MR-HC (flat cortisol profile) and treated with thrice-daily of conventional IR-HC (steep cortisol profile). The 24 hrs spontaneous oscillation of the clock genes in synchronized C2C12 cells was used to align the timing for in vitro HC exposure (Bmal1 acrophase, midphase and bathyphase) with the reference times of cortisol peaks in AI treated with IR-HC (8 am, 1 pm, 6 pm). A panel of 84 insulin sensitivity related genes and intracellular insulin signaling proteins were analyzed by RT-qPCR and western blot, respectively. Results: Only the steep profile, characterized by a higher HC exposure during Bmal1 bathyphase, produced significant downregulation in 21 insulin sensitivity-related genes. Among these, Insr, Irs1, Irs2, Pi3kca and Adipor2 were downregulated when compared the flat to the standard or steep profile. Reduced intracellular IRS1 Tyr608, AKT Ser473, AMPK Thr172 and ACC Ser79 phosphorylations were also observed. Conclusions: The current study demonstrated that is late-in-the-day cortisol exposure that modulates insulin sensitivity-related genes expression and intracellular insulin signaling in skeletal muscle cells.

scholarly journals CikA, an Input Pathway Component, Senses the Oxidized Quinone Signal to Generate Phase Delays in the Cyanobacterial Circadian Clock

2020 ◽  
Vol 35 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Pyonghwa Kim ◽  
Brianna Porr ◽  
Tetsuya Mori ◽  
Yong-Sung Kim ◽  
Carl H. Johnson ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Time Of Day ◽  
Fine Tuning ◽  
Circadian Oscillation ◽  
Clock Proteins ◽  
Entrainment Process ◽  
Central Oscillator ◽  
External Signals ◽  
Full Synchronization

The circadian clock is a timekeeping system in most organisms that keeps track of the time of day. The rhythm generated by the circadian oscillator must be constantly synchronized with the environmental day/night cycle to make the timekeeping system truly advantageous. In the cyanobacterial circadian clock, quinone is a biological signaling molecule used for entraining and fine-tuning the oscillator, a process in which the external signals are transduced into biological metabolites that adjust the phase of the circadian oscillation. Among the clock proteins, the pseudo-receiver domain of KaiA and CikA can sense external cues by detecting the oxidation state of quinone, a metabolite that reflects the light/dark cycle, although the molecular mechanism is not fully understood. Here, we show the antagonistic phase shifts produced by the quinone sensing of KaiA and CikA. We introduced a new cyanobacterial circadian clock mixture that includes an input component in vitro. KaiA and CikA cause phase advances and delays, respectively, in this circadian clock mixture in response to the quinone signal. In the entrainment process, oxidized quinone modulates the functions of KaiA and CikA, which dominate alternatively at day and night in the cell. This in turn changes the phosphorylation state of KaiC—the central oscillator in cyanobacteria—ensuring full synchronization of the circadian clock. Moreover, we reemphasize the mechanistic input functionality of CikA, contrary to other reports that focus only on its output action.

The Design and Synthesis of Novel Phenothiazine Derivatives as Potential Cytotoxic Agents

2019 ◽  
Vol 17 (1) ◽  
pp. 57-67
Author(s):  
Yepeng Luan ◽  
Jinyi Liu ◽  
Jianjun Gao ◽  
Jinhua Wang
Keyword(s):  
Cell Lines ◽  
High Efficiency ◽  
Human Cancer ◽  
Human Tumor ◽  
Cytotoxic Agents ◽  
Cancer Drug ◽  
Human Cancer Cell Lines ◽  
Incidence And Mortality ◽  
Anti Cancer

Background: Cancer incidence and mortality have been increasing and cancer is still the leading cause of death all over the world. Despite the enormous progress in cancer treatment, many patients died of ineffective chemotherapy and drug resistance. Therefore, the design and development of anti-cancer drugs with high efficiency and low toxicity is still one of the most challenging tasks. Tricyclic heterocycles, such as phenothiazine, are always important sources of scaffolds for anti-cancer drug discovery. Methods: In this work, ten new urea-containing derivatives of phenothiazine coupled with different kinds of amine motifs at the endpoint through a three carbon long spacer were designed and synthesized. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR and HRMS. All the synthesized compounds were tested for their antitumor activity in vitro against the proliferation of PC-3 cells, and the compounds with best potency entered further cytotoxicity evaluations against other 22 human tumor cell lines. Mechanism was also studied. Results: From all data, it showed that among all 10 target compounds, TTi-2 showed the best effect in inhibiting the proliferation of 23 human cancer cell lines while TTi-2 without obvious inhibitory effect on normal cell. Furthermore, our results also showed that TTi-2 could inhibit migration, invasion and colony formation of MDA-MB-231 cells. Finally, TTi-2 can induce arrest of cell cycle at G0/G1 phase and cell apoptosis by activating the caspase 3 activity. Conclusion: All these results suggested that TTi-2 might be used as a promising lead compound for anticancer drug development.

PREMONition: An algorithm for predicting the circadian clock-regulated molecular network

2018 ◽  
Author(s):  
Jasper Bosman ◽  
Zheng Eelderink-Chen ◽  
Emma Laing ◽  
Martha Merrow
Keyword(s):  
Circadian Clock ◽  
Clock Gene ◽  
Clock Genes ◽  
Circadian Clocks ◽  
Model Systems ◽  
Functional Relationships ◽  
Growth Assay ◽  
Living Organisms ◽  
Clock Mechanism ◽  
Transcriptional Feedback

AbstractA transcriptional feedback loop is central to clock function in animals, plants and fungi. The clock genes involved in its regulation are specific to - and highly conserved within - the kingdoms of life. However, other shared clock mechanisms, such as phosphorylation, are mediated by proteins found broadly among living organisms, performing functions in many cellular sub-systems. Use of homology to directly infer involvement/association with the clock mechanism in new, developing model systems, is therefore of limited use. Here we describe the approach PREMONition,PREdictingMolecularNetworks, that uses functional relationships to predict molecular circadian clock associations. PREMONition is based on the incorporation of proteins encoded by known clock genes (when available), rhythmically expressed clock-controlled genes and non-rhythmically expressed but interacting genes into a cohesive network. After tuning PREMONition on the networks derived for human, fly and fungal circadian clocks, we deployed the approach to predict a molecular clock network forSaccharomyces cerevisiae, for which there are no readily-identifiable clock gene homologs. The predicted network was validated using gene expression data and a growth assay for sensitivity to light, a zeitgeber of circadian clocks of most organisms. PREMONition may be used to identify candidate clock-regulated processes and thus candidate clock genes in other organisms.

scholarly journals An NF-κB–driven lncRNA orchestrates colitis and circadian clock

2020 ◽  
Vol 6 (42) ◽  
pp. eabb5202
Author(s):  
Shuai Wang ◽  
Yanke Lin ◽  
Feng Li ◽  
Zifei Qin ◽  
Ziyue Zhou ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Clock Gene ◽  
Clock Genes ◽  
Experimental Colitis ◽  
Circadian Clock Gene ◽  
Its Gene ◽  
E Box ◽  
Direct Binding ◽  
Central Clock ◽  
Clock Protein

We uncover a cycling and NF-κB–driven lncRNA (named Lnc-UC) that epigenetically modifies transcription of circadian clock gene Rev-erbα, thereby linking circadian clock to colitis. Cycling expression of Lnc-UC is generated by the central clock protein Bmal1 via an E-box element. NF-κB activation in experimental colitis transcriptionally drives Lnc-UC through direct binding to two κB sites. Lnc-UC ablation disrupts colonic expressions of clock genes in mice; particularly, Rev-erbα is down-regulated and its diurnal rhythm is blunted. Consistently, Lnc-UC promotes expression of Rev-erbα (a known dual NF-κB/Nlrp3 repressor) to inactivate NF-κB signaling and Nlrp3 inflammasome in macrophages. Furthermore, Lnc-UC ablation sensitizes mice to experimental colitis and abolishes the diurnal rhythmicity in disease severity. Mechanistically, Lnc-UC physically interacts with Cbx1 protein to reduce its gene silencing activity via H3K9me3, thereby enhancing Rev-erbα transcription and expression. In addition, we identify a human Lnc-UC that has potential to promote Rev-erbα expression and restrain inflammations.

scholarly journals The Molecular Evolution of Circadian Clock Genes in Spotted Gar (Lepisosteus oculatus)

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 622 ◽  
Author(s):  
Yi Sun ◽  
Chao Liu ◽  
Moli Huang ◽  
Jian Huang ◽  
Changhong Liu ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Teleost Fish ◽  
Clock Gene ◽  
Genome Duplication ◽  
Clock Genes ◽  
Gene Families ◽  
Regulatory Mechanisms ◽  
Spotted Gar ◽  
Circadian Clock Genes ◽  
Lepisosteus Oculatus

Circadian rhythms are biological rhythms with a period of approximately 24 h. While canonical circadian clock genes and their regulatory mechanisms appear highly conserved, the evolution of clock gene families is still unclear due to several rounds of whole genome duplication in vertebrates. The spotted gar (Lepisosteus oculatus), as a non-teleost ray-finned fish, represents a fish lineage that diverged before the teleost genome duplication (TGD), providing an outgroup for exploring the evolutionary mechanisms of circadian clocks after whole-genome duplication. In this study, we interrogated the spotted gar draft genome sequences and found that spotted gar contains 26 circadian clock genes from 11 families. Phylogenetic analysis showed that 9 of these 11 spotted gar circadian clock gene families have the same number of genes as humans, while the members of the nfil3 and cry families are different between spotted gar and humans. Using phylogenetic and syntenic analyses, we found that nfil3-1 is conserved in vertebrates, while nfil3-2 and nfil3-3 are maintained in spotted gar, teleost fish, amphibians, and reptiles, but not in mammals. Following the two-round vertebrate genome duplication (VGD), spotted gar retained cry1a, cry1b, and cry2, and cry3 is retained in spotted gar, teleost fish, turtles, and birds, but not in mammals. We hypothesize that duplication of core clock genes, such as (nfil3 and cry), likely facilitated diversification of circadian regulatory mechanisms in teleost fish. We also found that the transcription factor binding element (Ahr::Arnt) is retained only in one of the per1 or per2 duplicated paralogs derived from the TGD in the teleost fish, implicating possible subfuctionalization cases. Together, these findings help decipher the repertoires of the spotted gar’s circadian system and shed light on how the vertebrate circadian clock systems have evolved.

scholarly journals Oscillation of Clock and Clock Controlled Genes Induced by Serum Shock in Human Breast Epithelial and Breast Cancer Cells: Regulation by Melatonin

2012 ◽  
Vol 6 ◽  
pp. BCBCR.S9673 ◽  
Author(s):  
S. Xiang ◽  
L. Mao ◽  
T. Duplessis ◽  
L. Yuan ◽  
R. Dauchy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Clock Gene ◽  
Clock Genes ◽  
Horse Serum ◽  
Human Breast ◽  
Breast Epithelial ◽  
Mcf 7

This study investigates differences in expression of clock and clock-controlled genes (CCGs) between human breast epithelial and breast cancer cells and breast tumor xenografts in circadian intact rats and examines if the pineal hormone melatonin influences clock gene and CCG expression. Oscillation of clock gene expression was not observed under standard growth conditions in vitro, however, serum shock (50% horse serum for 2 h) induced oscillation of clock gene and CCG expression in MCF-10A cells, which was repressed or disrupted in MCF-7 cells. Melatonin administration following serum shock differentially suppressed or induced clock gene (Bmal1 and Per2) and CCG expression in MCF10A and MCF-7 cells. These studies demonstrate the lack of rhythmic expression of clock genes and CCGs of cells in vitro and that transplantation of breast cancer cells as xenografts into circadian competent hosts re-establishes a circadian rhythm in the peripheral clock genes of tumor cells.

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