Disruption of the circadian clock drives
            <i>Apc</i>
            loss of heterozygosity to accelerate colorectal cancer

Chun, Sung Kook; Fortin, Bridget M.; Fellows, Rachel C.; Habowski, Amber N.; Verlande, Amandine; Song, Wei A.; Mahieu, Alisa L.; Lefebvre, Austin E. Y. T.; Sterrenberg, Jason N.; Veléz, Leandro Martín; Digman, Michelle A.; Edwards, Robert A.; Pannunzio, Nicholas R.; Seldin, Marcus M.; Waterman, Marian L.; Masri, Selma

doi:10.1126/sciadv.abo2389

Cited by 52 publications

(51 citation statements)

References 119 publications

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“…The Wnt pathway has been implicated in aggressive HCC traits such as proliferation, invasion, chemoresistance, and cancer stem cell features [37]. A recent study demonstrated genetic disruption of the circadian clock hyperactivated Wnt signaling, thereby accelerating Apc-driven tumorigenesis [38]. In the current study, the circadian gene CSNK1D enhanced Wnt/β-catenin activity and downstream genes.…”

Section: Discussionmentioning

confidence: 48%

Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway via stabilizing Dishevelled Segment Polarity Protein 3

et al. 2022

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Purpose A variety of studies have connected circadian rhythm to the initiation and progression of hepatocellular carcinoma (HCC). The purpose of this study was to figure out about the circadian genes' profile characteristics, prognostic significance, and targeted values in HCC. Methods The expression profiles and prognostic significance of circadian genes in the cancer genome atlas liver hepatocellular carcinoma (TCGA-LIHC) database were investigated using bioinformatics analysis. The expression features of Casein Kinase 1 Delta (CSNK1D), a robust signature gene, was further detected by immunohistochemistry, western blotting and Real-time quantitative PCR (RT-qPCR) in a local HCC cohort. The effect of CSNK1D on corresponding phenotypes of HCC cells was evaluated using Cell Counting Kit-8 (CCK8), flowcytometry, clone assay, Transwell assay, and xenograft assay. In addition, the underlying mechanisms of CSNK1D in the Wnt/β-catenin signaling were validated by multiple molecular experiments. Results Abnormal expression of the Circadian genome was associated with the malignant clinicopathological characteristics of HCC patients. A 10 circadian gene-based signature with substantial prognostic significance was developed using Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. Of them, CSNK1D, significantly elevated in a local HCC cohort, was chosen for further investigation. Silencing or overexpression of CSNK1D significantly reduced or increased proliferation, invasion, sorafenib resistance, xenograft development, and epithelial-mesenchymal transformation (EMT) of HCC cells, respectively. Mechanically, CSNK1D exacerbated the aggressiveness of HCC cells by activating Wnt/β-catenin signaling through interacting with Dishevelled Segment Polarity Protein 3 (DVL3). Conclusions The Circadian gene CSNK1D was found to contribute to HCC progression by boosting the Wnt/β-catenin pathway, hinting that it could be a prospective therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 48%

Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway via stabilizing Dishevelled Segment Polarity Protein 3

et al. 2022

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“…However, the effect of clock disruption on tumorigenesis may be tissue and model-specific. For example, knock out of the core clock gene Bmal1 in mouse models of solid tumors promotes tumor progression in CRC (Chun, Fortin, Fellows et al, 2022;Stokes et al, 2021), lung (Papagiannakopoulos et al, 2016), and other cancer types (Lee et al, 2010) but reduces the development of cutaneous squamous tumors (Janich et al, 2011). Furthermore, downregulation of Bmal1 in human glioblastoma stem cells halts their growth (Dong et al, 2019;Puram et al, 2016).…”

Section: Circadian Clock Function In Various Tissues and Model Systemsmentioning

confidence: 99%

“…The focus of this review is on mammalian clocks and their roles in health and disease, with a particular focus on clocks in healthy versus transformed cells. Recent evidence has cited multiple diverse and tissue-specific functions of the circadian clock in different cancer types such as lung, colorectal, hepatocellular, breast, and others (Chun, Fortin, Fellows et al, 2022;Dong et al, 2019;Janich et al, 2011;Lee et al, 2010;Papagiannakopoulos et al, 2016;Puram et al, 2016;Stokes et al, 2021). This review will provide a comprehensive overview of the divergent functions of the clock in cell cycle control, maintenance of genome integrity, and immunity in healthy tissues, in an attempt to deconvolute the elaborate cellular networks that the biological pacemaker impinges on.…”

Section: Introductionmentioning

confidence: 99%

Circadian clocks in health and disease: Dissecting the roles of the biological pacemaker in cancer

et al. 2023

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In modern society, there is a growing population affected by circadian clock disruption through night shift work, artificial light-at-night exposure, and erratic eating patterns. Concurrently, the rate of cancer incidence in individuals under the age of 50 is increasing at an alarming rate, and though the precise risk factors remain undefined, the potential links between circadian clock deregulation and young-onset cancers is compelling. To explore the complex biological functions of the clock, this review will first provide a framework for the mammalian circadian clock in regulating critical cellular processes including cell cycle control, DNA damage response, DNA repair, and immunity under conditions of physiological homeostasis. Additionally, this review will deconvolute the role of the circadian clock in cancer, citing divergent evidence suggesting tissue-specific roles of the biological pacemaker in cancer types such as breast, lung, colorectal, and hepatocellular carcinoma. Recent evidence has emerged regarding the role of the clock in the intestinal epithelium, as well as new insights into how genetic and environmental disruption of the clock is linked with colorectal cancer, and the molecular underpinnings of these findings will be discussed. To place these findings within a context and framework that can be applied towards human health, a focus on how the circadian clock can be leveraged for cancer prevention and chronomedicine-based therapies will be outlined.

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“…The molecular circadian clock is tumor suppressive in many tissues. Indeed, disruption of the molecular clock, either by behavioral disruption or genetic mutation, can accelerate or initiate tumorigenesis in lung, liver, bone, colon, melanocyte, and other cell types [11][12][13][14][15][16][17][18][19]. Supporting the notion that the clock is tumor suppressive in human cancer, circadian gene expression is often disrupted in tumor tissue as compared to normal tissue [20].…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted January 3, 2023. ; https://doi.org/10.1101/2023.01.03.522637 doi: bioRxiv preprint tumorigenesis in lung, liver, bone, colon, melanocyte, and other cell types [11][12][13][14][15][16][17][18][19]. Supporting the notion that the clock is tumor suppressive in human cancer, circadian gene expression is often disrupted in tumor tissue as compared to normal tissue [20].…”

Section: Introductionmentioning

confidence: 99%

MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis

DeRollo

Cazarin

Shahidan

et al. 2023

Preprint

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The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites, is disrupted across many human cancers. Deregulated expression of MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC suppresses oscillation of gene expression and metabolism to instead upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC or the closely related N-MYC were examined, using detailed time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression, programs, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter glycosylation while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.

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Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer

Cited by 52 publications

References 119 publications

Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway via stabilizing Dishevelled Segment Polarity Protein 3

Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway via stabilizing Dishevelled Segment Polarity Protein 3

Circadian clocks in health and disease: Dissecting the roles of the biological pacemaker in cancer

MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis

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