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      Disruption of Planar Cell Polarity Pathway Attributable to Valproic Acid-Induced Congenital Heart Disease through Hdac3 Participation in Mice Translated title: 丙戊酸可通过组蛋白去乙酰化酶-3干扰平面细胞极性途 径导致先天性心脏病

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          Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway.


          VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay.


          VPA could induce CHD ( P < 0.001) and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression (all P < 0.05). In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression ( P < 0.01), while knockdown of Hdac1/2 had no influence ( P > 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity ( P < 0.01), while overexpression of Hdac3 could rescue the VPA-induced inhibition ( P > 0.05).


          VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.



          妊娠期丙戊酸(VPA)暴露被证实与先天性心脏病(CHD)发生有关。本团队前期实验研究发现,干扰心肌细胞平 面细胞极性(PCP)信号通路是VPA心脏致畸性的可能因素。此外,相关研究证实VPA的致畸作用与其对组蛋白去乙酰化酶 (HDAC)抑制作用成正相关。本研究旨在观察VPA对心脏形态发生、HDAC1/2/3及PCP通路关键基因(Vangl2/Scrib/Rac1) 的影响,进而筛选出参与PCP通路调控的特异性HDAC类型。


          以VPA 700mg/kg于妊娠第10.5天(E10.5)腹腔注射C57BL孕鼠。于E15.5处死孕鼠,统计胚胎死亡/流产率。采 集心脏标本以苏木精-伊红染色观察心脏畸形情况。以Hdac1/2/3特异性siRNA转染H9C2细胞(大鼠未分化心肌细 胞)。根据转染siRNA相关结果,以Hdac3表达质粒转染细胞,随后以假处理或VPA 8.0mmol/L干预细胞。分别采 用实时定量PCR及Western-blot检测Hdac1/2/3及Vangl2/Scrib/Rac1 mRNA及蛋白表达水平。利用比色法测定总 HDAC 活性。


          VPA可导致CHD( P<0.001),并下调胚胎心脏中Hdac1/2/3、Vangl2/Scrib/Rac1 mRNA及蛋白表达水平,同时抑制总 Hdac活性( P<0.05)。体外实验发现,抑制Hdac3可显著下调Vangl2/Scrib表达( P<0.01),而抑制Hdac1/2无以上作 用( P>0.05);VPA暴露可显著抑制Vanlg2/Scrib表达及Hdac活性 ( P<0.01),而过表达Hdac3可逆转VPA产生的抑制作用 ( P>0.05)。


          通过体外及体内实验我们均证实,VPA可抑制Hdac1/2/3、Vangl2/Scrib表达及总Hdac活性,并且Hdac3可 能参与VPA所致的心脏发育异常。

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          Most cited references 28

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          Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.

          Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.
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            HDAC family: What are the cancer relevant targets?

            Histone deacetylases comprise a family of 18 genes, which are grouped into classes I-IV based on their homology to their respective yeast orthologues. Classes I, II, and IV consist of 11 family members, which are referred to as "classical" HDACs, whereas the 7 class III members are called sirtuins. Classical HDACs are a promising novel class of anti-cancer drug targets. First HDAC inhibitors have been evaluated in clinical trials and show activity against several cancer diseases. However, these compounds act unselectively against several or all 11 HDAC family members. As a consequence, clinical phase I trials document a wide range of side effects. Therefore, the current challenge in the field is to define the cancer relevant HDAC family member(s) in a given tumor type and to design selective inhibitors, which target cancer cells but leave out normal cells. Knockout of single HDAC family members in mice produces a variety of phenotypes ranging from early embryonic death to viable animals with only discrete alterations, indicating that potential side effects of HDAC inhibitors depend on the selectivity of the compounds. Recently, several studies have shown that certain HDAC family members are aberrantly expressed in several tumors and have non-redundant function in controlling hallmarks of cancer cells. The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease.
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              Erasers of histone acetylation: the histone deacetylase enzymes.

              Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD(+)-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases.

                Author and article information

                [1 ]Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
                [2 ]Cardiac Development and Early Intervention Unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
                [3 ]Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan 610041, China
                [4 ]Key Laboratory of Development and Diseases of Women and Children of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
                Author notes
                Address for correspondence: Dr. Chuan Wang, Department of Pediatric Cardiovascular Disease, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Lu Road, Chengdu, Sichuan 610041, China E-Mail: chuanwang_d@
                Chin Med J (Engl)
                Chin. Med. J
                Chinese Medical Journal
                Medknow Publications & Media Pvt Ltd (India )
                05 September 2018
                : 131
                : 17
                : 2080-2088
                Copyright: © 2018 Chinese Medical Journal

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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