title: 5-Fluorouracil causes severe CNS demyelination by disruption of TCF7L2/HDAC1/HDAC2 complex in adolescent mice.
abstract: Several studies have showed the anti-cancer efficacy of 5-FU (5-fluorouracil) on pediatric tumors. Although the delayed demyelination induced by 5-FU in adult patients has been reported, the effect of 5-FU on oligodendrocyte myelination in adolescence is still unknown. Here, we demonstrate that systemic administration with 5-FU leads to immediate demyelination in the central nervous system (CNS) of adolescent mice, which is mainly attributed to the death of OLs. Gene-chip microarray transcriptome analysis identifies that oligodendrocyte-specific factor TCF7L2 may be a toxic target of 5-FU-impaired myelination. 5-FU-decreased TCF7L2 results in disruption of the interaction between TCF7L2 and HDAC1/2. Inhibition of crucial myelination-promoting factors by 5-FU is more significantly antagonized by co-transfection of TCF7L2, HDAC1 and HDAC2 than TCF7L2 alone. Our findings reveal that 5-FU could acutely induce the severe myelin degeneration in adolescence and disruption of TCF7L2/HDAC1/HDAC2 complex is at least partially involved in 5-FU-induced demyelination.
authors.affiliation: Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Center for Drug Safety Evaluation and Research, Zhejiang University, Hangzhou 310058, China. Electronic address: wengqinjie@zju.edu.cn.
authors.forename: Qinjie
authors.initials: Q
authors.lastname: Weng
authors.affiliation: Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Biqin
authors.initials: B
authors.lastname: Tan
authors.affiliation: Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of Pediatrics and Obstetrics/Gynecology, Institute of Stem Cell and Developmental Biology, West China Second Hospital, Chengdu 61004, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Departments of Pediatrics and Obstetrics/Gynecology, Institute of Stem Cell and Developmental Biology, West China Second Hospital, Chengdu 61004, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Center for Drug Safety Evaluation and Research, Zhejiang University, Hangzhou 310058, China.
authors.forename: QiaoJun
authors.initials: Q
authors.lastname: He
authors.affiliation: Institute of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D000367:Age Factors; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes; D009836:Oligodendroglia / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000964:Antimetabolites, Antineoplastic; D046912:Multiprotein Complexes; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D005472:Fluorouracil
keywords: 5-FU; Adolescence; Demyelination; Oligodendrocyte; TCF7L2