Cargando…

Evidence for widespread dysregulation of circadian clock progression in human cancer

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 tissu...

Descripción completa

Detalles Bibliográficos
Autores principales: Shilts, Jarrod, Chen, Guanhua, Hughey, Jacob J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797448/
https://www.ncbi.nlm.nih.gov/pubmed/29404219
http://dx.doi.org/10.7717/peerj.4327
_version_ 1783297688734793728
author Shilts, Jarrod
Chen, Guanhua
Hughey, Jacob J.
author_facet Shilts, Jarrod
Chen, Guanhua
Hughey, Jacob J.
author_sort Shilts, Jarrod
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5797448
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher PeerJ Inc.
record_format MEDLINE/PubMed
spelling pubmed-57974482018-02-05 Evidence for widespread dysregulation of circadian clock progression in human cancer Shilts, Jarrod Chen, Guanhua Hughey, Jacob J. PeerJ Bioinformatics 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. PeerJ Inc. 2018-01-31 /pmc/articles/PMC5797448/ /pubmed/29404219 http://dx.doi.org/10.7717/peerj.4327 Text en ©2018 Shilts et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Bioinformatics
Shilts, Jarrod
Chen, Guanhua
Hughey, Jacob J.
Evidence for widespread dysregulation of circadian clock progression in human cancer
title Evidence for widespread dysregulation of circadian clock progression in human cancer
title_full Evidence for widespread dysregulation of circadian clock progression in human cancer
title_fullStr Evidence for widespread dysregulation of circadian clock progression in human cancer
title_full_unstemmed Evidence for widespread dysregulation of circadian clock progression in human cancer
title_short Evidence for widespread dysregulation of circadian clock progression in human cancer
title_sort evidence for widespread dysregulation of circadian clock progression in human cancer
topic Bioinformatics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797448/
https://www.ncbi.nlm.nih.gov/pubmed/29404219
http://dx.doi.org/10.7717/peerj.4327
work_keys_str_mv AT shiltsjarrod evidenceforwidespreaddysregulationofcircadianclockprogressioninhumancancer
AT chenguanhua evidenceforwidespreaddysregulationofcircadianclockprogressioninhumancancer
AT hugheyjacobj evidenceforwidespreaddysregulationofcircadianclockprogressioninhumancancer