{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T01:23:14Z","timestamp":1785201794843,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2013,12,4]],"date-time":"2013-12-04T00:00:00Z","timestamp":1386115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hepatocarcinogenesis is associated with epigenetic changes, including histone deacetylases (HDACs). Epigenetic modulation by HDAC inhibition is a potentially valuable approach for hepatocellular carcinoma treatment. In present study, we evaluated the anticancer effects of sodium valproate (SVP), a known HDAC inhibitor, in human hepatocarcinoma cells. The results showed SVP inhibited the proliferation of Bel-7402 cells in a dose-dependent manner. Low dose SVP treatment caused a large and flat morphology change, positive SA-\u03b2-gal staining, and G0\/G1 phase cell cycle arrest in human hepatocarcinoma cells. Low dose SVP treatment also increased acetylation of histone H3 and H4 on p21 promoter, accompanied by up-regulation of p21 and down-regulation of RB phosphorylation. These observations suggested that a low dose of SVP could induce cell senescence in hepatocarcinoma cells, which might correlate with hyperacetylation of histone H3 and H4, up-regulation of p21, and inhibition of RB phosphorylation. Since the effective concentration inducing cell senescence in hepatocarcinoma cells is clinically available, whether a clinical dose of SVP could induce cell senescence in clinical hepatocarcinoma is worthy of further study.<\/jats:p>","DOI":"10.3390\/molecules181214935","type":"journal-article","created":{"date-parts":[[2013,12,4]],"date-time":"2013-12-04T12:02:38Z","timestamp":1386158558000},"page":"14935-14947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Sodium Valproate Induces Cell Senescence in Human Hepatocarcinoma Cells"],"prefix":"10.3390","volume":"18","author":[{"given":"Hong-Mei","family":"An","sequence":"first","affiliation":[{"name":"Department of Science and Technology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Fei","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Oncology, Center Hospital of Nanyang, Nanyang, Henan 473000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Li","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Oncology, Center Hospital of Nanyang, Nanyang, Henan 473000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China"},{"name":"Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China"},{"name":"Institute of Traditional Chinese Medicine in Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 202032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3322\/caac.20107","article-title":"Global cancer statistics","volume":"61","author":"Jemal","year":"2011","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1556\/oh.2008.28313","article-title":"Epidemiology risk factors and molecular pathogenesis of primary liver cancer","volume":"149","author":"Tulassay","year":"2008","journal-title":"Orv. Hetil."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s11912-010-0094-3","article-title":"Current management of hepatocellular cancer","volume":"12","author":"Rampone","year":"2010","journal-title":"Curr. Oncol. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1177\/145749691110000105","article-title":"Treatment options in hepatocellular carcinoma today","volume":"100","author":"Livraghi","year":"2011","journal-title":"Scand. J. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1056\/NEJMra1001683","article-title":"Current concepts: Hepatocellular carcinoma","volume":"365","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.mrrev.2011.04.001","article-title":"Epigenetic mechanisms in hepatocellular carcinoma: How environmental factors influence the epigenome","volume":"727","author":"Herceg","year":"2011","journal-title":"Mutat. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1002\/hep.23388","article-title":"Hepatitis C virus-induced up-regulation of protein phosphatase 2A inhibits histone modification and DNA damage repair","volume":"51","author":"Duong","year":"2010","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1038\/sj.onc.1211000","article-title":"Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells","volume":"27","author":"Yoo","year":"2008","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1159\/000111106","article-title":"Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma","volume":"72","author":"Rikimaru","year":"2007","journal-title":"Oncology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00428-011-1103-0","article-title":"Clinical significance of histone deacetylases 1, 2, 3, and 7: HDAC2 is an independent predictor of survival in HCC","volume":"459","author":"Quint","year":"2011","journal-title":"Virchows Arch."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.1093\/emboj\/20.24.6969","article-title":"Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells","volume":"20","author":"Minucci","year":"2001","journal-title":"EMBO J."},{"key":"ref_12","first-page":"25","article-title":"Expressional changes after histone deacetylase inhibition by valproic acid in LNCaP human prostate cancer cells","volume":"24","author":"Thelen","year":"2004","journal-title":"Int. J. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1158\/1078-0432.CCR-03-0100","article-title":"Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells","volume":"10","author":"Takai","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1210\/jc.2004-1355","article-title":"Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells","volume":"90","author":"Catalano","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","first-page":"573","article-title":"Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines","volume":"30","author":"Schwartz","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/1756-9966-29-149","article-title":"Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line","volume":"29","author":"Yagi","year":"2010","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1158\/1535-7163.MCT-05-0184","article-title":"Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC","volume":"4","author":"Li","year":"2005","journal-title":"Mol. Cancer Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/hed.21734","article-title":"Valproic acid: Growth inhibition of head and neck cancer by induction of terminal differentiation and senescence","volume":"34","author":"Gan","year":"2012","journal-title":"Head Neck"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.4149\/neo_2011_01_35","article-title":"Epigenetic modulation of gene expression of human leukemia cell lines\u2014Induction of cell death and senescence","volume":"58","author":"Elknerova","year":"2011","journal-title":"Neoplasma"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9363","DOI":"10.1073\/pnas.92.20.9363","article-title":"A biomarker that identifies senescent human cells in culture and in aging skin in vivo","volume":"92","author":"Dimri","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"287","DOI":"10.2174\/092986709787002691","article-title":"Senescence and cell death pathways and their role in cancer therapeutic outcome","volume":"16","author":"Chiantore","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_22","first-page":"5","article-title":"Cellular senescence and cancer treatment","volume":"1775","author":"Schmitt","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.bcp.2008.06.024","article-title":"Accelerated senescence: An emerging role in tumor cell response to chemotherapy and radiation","volume":"76","author":"Gewirtz","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/j.bcp.2008.12.016","article-title":"Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to adriamycin","volume":"77","author":"Di","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","first-page":"1876","article-title":"DNA damage is able to induce senescence in tumor cells in vitro and in vivo","volume":"62","author":"Okorokov","year":"2002","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17154","DOI":"10.1074\/jbc.M112401200","article-title":"Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin","volume":"277","author":"Han","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_27","first-page":"2705","article-title":"Tumor cell senescence in cancer treatment","volume":"63","author":"Roninson","year":"2003","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.ccr.2005.05.025","article-title":"What has senescence got to do with cancer","volume":"7","author":"Dimri","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/0092-8674(93)90500-P","article-title":"WAF1, a potential mediator of p53 tumor suppression","volume":"75","author":"Tokino","year":"1993","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.biocel.2007.03.001","article-title":"Histone deacetylase inhibitors: Signalling towards p21cip1\/waf1","volume":"39","author":"Ocker","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1158\/0008-5472.CAN-07-5807","article-title":"Statins increase p21 through inhibition of histone deacetylase activity and release of promoter-associated HDAC1\/2","volume":"68","author":"Lin","year":"2008","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e28103","DOI":"10.1371\/journal.pone.0028103","article-title":"Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1\/S cell cycle proteins","volume":"6","author":"Noh","year":"2011","journal-title":"PLoS One"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1073\/pnas.0307708100","article-title":"Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1","volume":"101","author":"Gui","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","first-page":"1465","article-title":"Modified Yi Guan Jian, a Chinese herbal formula, induces anoikis in Bel-7402 human hepatocarcinoma cells in vitro","volume":"26","author":"Hu","year":"2011","journal-title":"Oncol. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3892\/etm.2011.364","article-title":"Liver Yin deficiency tonifying herbal extract induces apoptosis and cell senescence in Bel-7402 human hepatocarcinoma cells","volume":"3","author":"Hu","year":"2012","journal-title":"Exp. Ther. Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/12\/14935\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:51:06Z","timestamp":1760219466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/12\/14935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,4]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2013,12]]}},"alternative-id":["molecules181214935"],"URL":"https:\/\/doi.org\/10.3390\/molecules181214935","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,4]]}}}