Document Type
Article
Publication Date
2019
College/Unit
Eberly College of Arts and Sciences
Department/Program/Center
Microbiology, Immunology, and Cell Biology
Abstract
The cell cycle is under circadian regulation. Oncogenes can dysregulate circadian-regulated genes to disrupt the cell cycle, promoting tumor cell proliferation. As a regulator of G2/M arrest in response to DNA damage, the circadian gene Timeless Circadian Clock (TIMELESS) coordinates this connection and is a potential locus for oncogenic manipulation. TIMELESS expression was evaluated using RNASeq data from TCGA and by RT-qPCR and western blot analysis in a panel of colon cancer cell lines. TIMELESS expression following ERK inhibition was examined via western blot. Cell metabolic capacity, propidium iodide, and CFSE staining were used to evaluate the effect of TIMELESS depletion on colon cancer cell survival and proliferation. Cell metabolic capacity following TIMELESS depletion in combination with Wee1 or CHK1 inhibition was assessed. TIMELESS is overexpressed in cancer and required for increased cancer cell proliferation. ERK activation promotes TIMELESS expression. TIMELESS depletion increases γH2AX, a marker of DNA damage, and triggers G2/M arrest via increased CHK1 and CDK1 phosphorylation. TIMELESS depletion in combination with Wee1 or CHK1 inhibition causes an additive decrease in cancer cell metabolic capacity with limited effects in non-transformed human colon epithelial cells. The data show that ERK activation contributes to the overexpression of TIMELESS in cancer. Depletion of TIMELESS increases γH2AX and causes G2/M arrest, limiting cell proliferation. These results demonstrate a role for TIMELESS in cancer and encourage further examination of the link between circadian rhythm dysregulation and cancer cell proliferation.
Digital Commons Citation
Neilsen, Beth K.; Frodyma, Danielle E.; McCall, Jaime L.; Fisher, Kurt W.; and Lewis, Robert E., "ERK-mediated TIMELESS expression suppresses G2/M arrest in colon cancer cells" (2019). Faculty & Staff Scholarship. 2359.
https://researchrepository.wvu.edu/faculty_publications/2359
Source Citation
Neilsen BK, Frodyma DE, McCall JL, Fisher KW, Lewis RE (2019) ERK-mediated TIMELESS expression suppresses G2/M arrest in colon cancer cells. PLoS ONE 14(1): e0209224. https://doi.org/10.1371/journal.pone.0209224
Comments
© 2019 Neilsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.