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Mol Cell Endocrinol. 2014 Mar 5;383(1-2):147-58. doi: 10.1016/j.mce.2013.12.008. Epub 2013 Dec 19.

Valproic acid enhances Oct4 promoter activity through PI3K/Akt/mTOR pathway activated nuclear receptors.

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Department of Life Sciences, National Central University, Jhongli 32001, Taiwan.
Department of Chemistry, National Central University, Jhongli 32001, Taiwan.
Department of Biochemistry, Chang Gung University, Taoyuan 333, Taiwan.
Department of Life Sciences, National Central University, Jhongli 32001, Taiwan. Electronic address:


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.


Akt; Muscle; Nuclear receptor; Oct4; VPA; iPSC

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