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Impairment of liver regeneration by the histone deacetylase inhibitor valproic acid in mice

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Abstract

Background and objective: Liver regeneration is a complex process regulated by a group of genetic and epigenetic factors. A variety of genetic factors have been reported, whereas few investigations have focused on epigenetic regulation during liver regeneration. In the present study, valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, was used to investigate the effect of HDAC on liver regeneration. Methods: VPA was administered via intraperitoneal injection to 2/3 partially hepatectomized mice to detect hepatocyte proliferation during liver regeneration. The mice were sacrificed, and their liver tissues were harvested at sequential time points from 0 to 168 h after treatment. DNA synthesis was detected via a BrdU assay, and cell proliferation was tested using Ki-67. The expressions of cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), and CDK4 were detected by Western blot analysis. Chromatin immunoprecipitation (ChIP) assay was used to examine the recruitment of HDACs to the target promoter regions and the expression of the target gene was detected by Western blot. Results: Immunohistochemical analysis showed that cells positive for BrdU and Ki-67 decreased, and the peak of BrdU was delayed in the VPA-administered mice. Consistently, cyclin D1 expression was also delayed. We identified B-myc as a target gene of HDACs by complementary DNA (cDNA) microarray. The expression of B-myc increased in the VPA-administered mice after hepatectomy (PH). The ChIP assay confirmed the presence of HDACs at the B-myc promoter. Conclusions: HDAC activities are essential for liver regeneration. Inhibiting HDAC activities delays liver regeneration and induces liver cell cycle arrest, thereby causing an anti-proliferative effect on liver regeneration.

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Authors and Affiliations

  1. Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Qi Ke, Feng Ye & Hong Bu

  2. Department of Oncology, the First Affiliated Hospital, Henan University of Science and Technology, Luoyang, 471003, China

    Rui-na Yang

  3. Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu, 610041, China

    Rui-na Yang, Yu-jia Wang, Qiong Wu & Li Li

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  1. Qi Ke
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Correspondence to Hong Bu.

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Project (Nos. 30971118 and 31000601) supported by the National Natural Science Foundation of China

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Ke, Q., Yang, Rn., Ye, F. et al. Impairment of liver regeneration by the histone deacetylase inhibitor valproic acid in mice. J. Zhejiang Univ. Sci. B 13, 695–706 (2012). https://doi.org/10.1631/jzus.B1100362

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  • DOI: https://doi.org/10.1631/jzus.B1100362

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