title: Valproic acid enhances Oct4 promoter activity through PI3K/Akt/mTOR pathway activated nuclear receptors.
abstract: Valproic acid (VPA) has been shown to increase the reprogramming efficiency of induced pluripotent stem cells (iPSC) from somatic cells, but the mechanism by which VPA enhances iPSC induction has not been defined. Here we demonstrated that VPA directly activated Oct4 promoter activity through activation of the PI3K/Akt/mTOR signaling pathway that targeted the proximal hormone response element (HRE, -41∼-22) in this promoter. The activating effect of VPA is highly specific as similar compounds or constitutional isomers failed to instigate Oct4 promoter activity. We further demonstrated that the upstream 2 half-sites in this HRE were essential to the activating effect of VPA and they were targeted by a subset of nuclear receptors, such as COUP-TFII and TR2. These findings show the first time that NRs are implicated in the VPA stimulated expression of stem cell-specific factors and should invite more investigation on the cooperation between VPA and NRs on iPSC induction.
authors.affiliation: Department of Life Sciences, National Central University, Jhongli 32001, Taiwan.
authors.forename: Han Fang
authors.initials: HF
authors.lastname: Teng
authors.affiliation: Department of Life Sciences, National Central University, Jhongli 32001, Taiwan.
authors.forename: Pei Ning
authors.initials: PN
authors.lastname: Li
authors.affiliation: Department of Chemistry, National Central University, Jhongli 32001, Taiwan.
authors.forename: Duen Ren
authors.initials: DR
authors.lastname: Hou
authors.affiliation: Department of Chemistry, National Central University, Jhongli 32001, Taiwan.
authors.forename: Sin Wei
authors.initials: SW
authors.lastname: Liu
authors.affiliation: Department of Life Sciences, National Central University, Jhongli 32001, Taiwan.
authors.forename: Cheng Tao
authors.initials: CT
authors.lastname: Lin
authors.affiliation: Department of Life Sciences, National Central University, Jhongli 32001, Taiwan.
authors.forename: Moo Rung
authors.initials: MR
authors.lastname: Loo
authors.affiliation: Department of Life Sciences, National Central University, Jhongli 32001, Taiwan.
authors.forename: Chien Han
authors.initials: CH
authors.lastname: Kao
authors.affiliation: Department of Biochemistry, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Kwang Huei
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Department of Life Sciences, National Central University, Jhongli 32001, Taiwan. Electronic address: slchen@cc.ncu.edu.tw.
authors.forename: Shen Liang
authors.initials: SL
authors.lastname: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D051837:COUP Transcription Factor II / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D005786:Gene Expression Regulation; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1 / Q000235:genetics* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D051837:COUP Transcription Factor II; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D050814:Octamer Transcription Factor-3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014635:Valproic Acid; C497587:Nr2f2 protein, mouse; C494174:Pou5f1 protein, mouse; C546842:MTOR protein, human
keywords: Akt; Muscle; Nuclear receptor; Oct4; VPA; iPSC