title: Epigenomics alternations and dynamic transcriptional changes in responses to 5-fluorouracil stimulation reveal mechanisms of acquired drug resistance of colorectal cancer cells.
abstract: A drug-induced resistant cancer cell is different from its parent cell in transcriptional response to drug treatment. The distinct transcriptional response pattern of a drug-induced resistant cancer cell to drug treatment might be introduced by acquired DNA methylation aberration in the cell exposing to sustained drug stimulation. In this study, we performed both transcriptional and DNA methylation profiles of the HCT-8 wild-type cells (HCT-8/WT) for human colorectal cancer (CRC) and the 5-fluorouracil (5-FU)-induced resistant cells (HCT-8/5-FU) after treatment with 5-FU for 0, 24 and 48 h. Integrated analysis of transcriptional and DNA methylation profiles showed that genes with promoter hypermethylation and concordant expression silencing in the HCT-8/5-FU cells are mainly involved in pathways of pyrimidine metabolism and drug metabolism-cytochrome P450. Transcriptional analysis confirmed that genes with transcriptional differences between a drug-induced resistant cell and its parent cell after drug treatment for a certain time, rather than their primary transcriptional differences, are more likely to be involved in drug resistance. Specifically, transcriptional differences between the drug-induced resistant cells and parental cells after drug treatment for 24 h were significantly consistent with the differentially expressed genes (termed as CRG5-FU) between the tissues of nonresponders and responders of CRCs to 5-FU-based therapy and the consistence increased after drug treatment for 48 h (binomial test, P-value=1.88E-06). This study reveals a major epigenetic mechanism inducing the HCT-8/WT cells to acquire resistance to 5-FU and suggests an appropriate time interval (24-48 h) of 5-FU exposure for identifying clinically relevant drug resistance signatures from drug-induced resistant cell models.
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Department of Preventive Medicine, School of Basic Medicine Sciences, Gannan Medical University, Ganzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: H Q
authors.initials: HQ
authors.lastname: Sun
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Ao
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Bioinformatics, Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
authors.forename: F
authors.initials: F
authors.lastname: She
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics; D057890:Epigenomics / Q000379:methods; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics*
chemical_list: D005472:Fluorouracil