Chang, WH;
Lai, AG;
(2019)
Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies.
Journal of Translational Medicine
, 17
, Article 132. 10.1186/s12967-019-1880-9.
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Timing gone awry distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signallin.pdf - Published Version Download (8MB) | Preview |
Abstract
Background: The circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pan-cancer evidence supporting this notion has been limited. Methods: In an integrated approach uniting genomic, transcriptomic and clinical data of 21 cancer types (n=18,484), we interrogated copy number and transcript profles of 32 circadian clock genes to identify putative lossof-function (ClockLoss) and gain-of-function (ClockGain) players. Kaplan–Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic signifcance of both gene sets. Results: ClockLoss and ClockGain were associated with tumour-suppressing and tumour-promoting roles respectively. Downregulation of ClockLoss genes resulted in signifcantly higher mortality rates in fve cancer cohorts (n=2914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach (P=0.0007). In contrast, patients with high expression of oncogenic ClockGain genes had poorer survival outcomes (n=2784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas (P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may infuence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive ClockLoss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis. Conclusions: Loss of timekeeping fdelity promotes tumour progression and infuences clinical outcomes. ClockLoss and ClockGain may ofer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratifcation in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with frst-line treatments.
| Type: | Article |
|---|---|
| Title: | Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12967-019-1880-9 |
| Publisher version: | https://doi.org/10.1186/s12967-019-1880-9 |
| Language: | English |
| Additional information: | This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made |
| Keywords: | Circadian clock, Hypoxia, Oncogene, Tumour suppressor, Gain-of-function, Loss-of-function, Pan-cancer, Glioma, Renal cancer |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10079650 |
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