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Molecular Cancer Research
Molecular Cancer Research
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Cancer Genes and Networks

Circadian Oscillations Persist in Cervical and Esophageal Cancer Cells Displaying Decreased Expression of Tumor-Suppressing Circadian Clock Genes

Pauline J. van der Watt, Laura C. Roden, Kate T. Davis, M. Iqbal Parker and Virna D. Leaner
Pauline J. van der Watt
1Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
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  • For correspondence: Pauline.vanderwatt@uct.ac.za
Laura C. Roden
2School of Life Sciences, Coventry University, Coventry, United Kingdom.
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  • ORCID record for Laura C. Roden
Kate T. Davis
1Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
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M. Iqbal Parker
1Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
3Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
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Virna D. Leaner
1Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
3Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
4SAMRC/UCT Gynaecological Cancer Research Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
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DOI: 10.1158/1541-7786.MCR-19-1074 Published September 2020
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Abstract

There is accumulating evidence for a link between circadian clock disruption and cancer progression. In this study, the circadian clock was investigated in cervical and esophageal cancers, to determine whether it is disrupted in these cancer types. Oncomine datamining revealed downregulation of multiple members of the circadian clock gene family in cancer patient tissue compared with matched normal epithelium. Real-time RT-PCR analysis confirmed significant downregulation of CLOCK, PER1, PER2, PER3, CRY1, CRY2, REV-ERBα, and RORα in esophageal tumor tissue. In cell line models, expression of several circadian clock genes was significantly decreased in transformed and cancer cells compared with noncancer controls, and protein levels were dysregulated. These effects were mediated, at least in part, by methylation, where CLOCK, CRY1, and RORα gene promoter regions were found to be methylated in cancer cells. Overexpression of CLOCK and PER2 in cancer cell lines inhibited cell proliferation and activation of RORα and REV-ERBα using agonists resulted in cancer cell death, while having a lesser effect on normal epithelial cells. Despite dysregulated circadian clock gene expression, cervical and esophageal cancer cells maintain functional circadian oscillations after Dexamethasone synchronization, as revealed using real-time bioluminescence imaging, suggesting that their circadian clock mechanisms are intact.

Implications: This study is a first to describe dysregulated, yet oscillating, circadian clock gene expression in cervical and esophageal cancer cells, and knowledge of circadian clock functioning in these cancer types has the potential to inform chronotherapy approaches, where the timing of administration of chemotherapy is optimized on the basis of the circadian clock.

This article is featured in Highlights of This Issue, p. 1255

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1340–53

  • Received November 1, 2019.
  • Revision received April 1, 2020.
  • Accepted June 2, 2020.
  • Published first June 5, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (9)
September 2020
Volume 18, Issue 9
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Circadian Oscillations Persist in Cervical and Esophageal Cancer Cells Displaying Decreased Expression of Tumor-Suppressing Circadian Clock Genes
Pauline J. van der Watt, Laura C. Roden, Kate T. Davis, M. Iqbal Parker and Virna D. Leaner
Mol Cancer Res September 1 2020 (18) (9) 1340-1353; DOI: 10.1158/1541-7786.MCR-19-1074

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Circadian Oscillations Persist in Cervical and Esophageal Cancer Cells Displaying Decreased Expression of Tumor-Suppressing Circadian Clock Genes
Pauline J. van der Watt, Laura C. Roden, Kate T. Davis, M. Iqbal Parker and Virna D. Leaner
Mol Cancer Res September 1 2020 (18) (9) 1340-1353; DOI: 10.1158/1541-7786.MCR-19-1074
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Molecular Cancer Research
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