FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression

File Description SizeFormat 
s41598-018-38017-0.pdfPublished version8.84 MBAdobe PDFView/Open
Title: FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression
Authors: Varghese, V
Magnani, L
Harada, N
Mauri, F
Szydlo, R
Yao, S
Lam, E
Kenny, L
Item Type: Journal Article
Abstract: Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
Issue Date: 6-Feb-2019
Date of Acceptance: 7-Oct-2018
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 9
Copyright Statement: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre-ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per-mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
Sponsor/Funder: Breast Cancer Now
Breast Cancer Now
Medical Research Council (MRC)
Cancer Research UK
National Institute for Health Research
Funder's Grant Number: 2012NovemberPhD016
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
Publication Status: Published
Article Number: ARTN 1505
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commonsx