Dataset Information

Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion.

ABSTRACT: Although dysfunctional circadian clock has emerged as a hallmark of cancer, fundamental gaps remain in our understanding of the underlying mechanisms involved. Here, we systematically analyze the core genes of the circadian clock (CLOCK, ARNTL, ARNTL2, NPAS2, NR1D1, NR1D2, CRY1, CRY2, RORA, RORB, RORC, PER1, PER2, and PER3) across a broad range of cancers. To our surprise, core negative regulators (PER1, PER2, PER3, CRY1, and CRY2) are consistently downregulated, while core positive regulators show minimal alterations, indicating disrupted circadian clock in cancers. Such downregulation originates from copy number variations where heterozygous deletion predominates. The disrupted circadian clock is significantly associated with patient outcome. Further pathway enrichment analysis suggests that the circadian clock widely impacts 45 pathways such as the Ras signaling pathway and T cell receptor signaling pathway. By using state-of-the-art immune cell deconvolution and pathway quantification, we demonstrate that abnormal circadian clock contributes to T cell exhaustion and global upregulation of immune inhibitory molecules such as PD-L1 and CTLA-4. In summary, the rhythm of the circadian clock is disrupted in cancers. Abnormal circadian clock linked with immune evasion may serve as a potential hallmark of cancer.

SUBMITTER: Wu Y

PROVIDER: S-EPMC6821711 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion.

Wu Yingcheng Y Tao Baorui B Zhang Tianyang T Fan Yihui Y Mao Renfang R

Frontiers in immunology 20191024

Although dysfunctional circadian clock has emerged as a hallmark of cancer, fundamental gaps remain in our understanding of the underlying mechanisms involved. Here, we systematically analyze the core genes of the circadian clock (CLOCK, ARNTL, ARNTL2, NPAS2, NR1D1, NR1D2, CRY1, CRY2, RORA, RORB, RORC, PER1, PER2, and PER3) across a broad range of cancers. To our surprise, core negative regulators (PER1, PER2, PER3, CRY1, and CRY2) are consistently downregulated, while core positive regulators s ...[more]

PMID: 31708917

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Project description:Background: Pan-renal cell carcinoma (pan-RCC) is mainly divided into renal clear cell carcinoma (KIRC), renal papillary cell carcinoma (KIRP), and chromophobe cell carcinoma (KICH). Pan-RCC is a common malignant neoplasm with a high incidence and poor prognosis. Several studies have demonstrated a close association between cancer development and circadian rhythms; however, the clinical significance and molecular mechanism of the clock gene remain unclear in pan-RCC. Methods: In this study, we systematically characterized the alterations of 15 well-known clock genes of three types of kidney cancer. Bioinformatics methods, including differential expression analysis, survival analysis, signing pathway analysis, co-expression network analysis, and drug sensitivity analysis were used to study the diagnosis, prognostic role, and mechanism of clock genes. Results: Thirteen rhythmic genes fluctuated in circadian rhythm in the kidney tissue of mice, and the opposite trend of these rhythm phases was also found in baboons. There are twelve clock genes that were differentially expressed in at least two types of RCC, of which NR1D1, DBP, BHLHE40, CRY1, and CLOCK had the same trend in RCC. Changes in clock control genes may be regulated through methylation, copy number, and mutations. Five rhythmic genes, including PER2, DBP, PER3, CRY2, and RORA, have significant prognostic role in patient survival in at least two types of kidney cancer. Immune infiltration analysis showed that the expression of these rhythmic genes related to prognosis was positively correlated with the infiltration levels of CD4 and CD8 T cells. Pathway analysis suggests that the clock genes is widely related to cancer-related signaling pathways, such as apoptosis, cell cycle, and other pathways. The PPI network showed that circadian genes are closely linked to cancer-related genes such as HIF-1A, TP53, and ERBB2. Moreover, clock gene expression is correlated with the sensitivity of anticancer drugs such as bleomycin and methotrexate in pan-RCC. Conclusion: Taken together, the abnormal expression of biological clock genes plays an important role in the clinical prognosis of RCC through immunity, cell cycle, and apoptosis. These findings provide a reliable basis for the diagnosis, prognosis, and drug guidance for RCC.

Project description:BackgroundTranscriptional feedback loops are central to circadian clock function. However, the role of neural activity and membrane events in molecular rhythms in the fruit fly Drosophila is unclear. To address this question, we expressed a temperature-sensitive, dominant negative allele of the fly homolog of dynamin called shibire(ts1) (shi(ts1)), an active component in membrane vesicle scission.Principal findingsBroad expression in clock cells resulted in unexpectedly long, robust periods (>28 hours) comparable to perturbation of core clock components, suggesting an unappreciated role of membrane dynamics in setting period. Expression in the pacemaker lateral ventral neurons (LNv) was necessary and sufficient for this effect. Manipulation of other endocytic components exacerbated shi(ts1)'s behavioral effects, suggesting its mechanism is specific to endocytic regulation. PKA overexpression rescued period effects suggesting shi(ts1) may downregulate PKA pathways. Levels of the clock component PERIOD were reduced in the shi(ts1)-expressing pacemaker small LNv of flies held at a fully restrictive temperature (29 degrees C). Less restrictive conditions (25 degrees C) delayed cycling proportional to observed behavioral changes. Levels of the neuropeptide PIGMENT-DISPERSING FACTOR (PDF), the only known LNv neurotransmitter, were also reduced, but PERIOD cycling was still delayed in flies lacking PDF, implicating a PDF-independent process. Further, shi(ts1) expression in the eye also results in reduced PER protein and per and vri transcript levels, suggesting that shibire-dependent signaling extends to peripheral clocks. The level of nuclear CLK, transcriptional activator of many core clock genes, is also reduced in shi(ts1) flies, and Clk overexpression suppresses the period-altering effects of shi(ts1).ConclusionsWe propose that membrane protein turnover through endocytic regulation of PKA pathways modulates the core clock by altering CLK levels and/or activity. These results suggest an important role for membrane scission in setting circadian period.

Dataset Information

Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion.

Publications

Pan-Cancer Analysis Reveals Disrupted Circadian Clock Associates With T Cell Exhaustion.

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