Histone deacetylases (HDACs) are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC), but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21WAF1/Cip1 and p27Kip1 expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21WAF1/Cip1 transcriptional activity through Sp1-binding sites in the p21WAF1/Cip1 promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy.
References
[1]
Yang JD, Roberts LR (2010) Hepatocellular carcinoma: a global view. Nature Reviews Gastroenterology & Hepatology 7: 448–458.
[2]
Iakova P, Timchenko L, Timchenko NA (2011) Intracellular signaling and hepatocellular carcinoma. Semin Cancer Biol 21: 28–34.
[3]
Ropero S, Esteller M (2007) The role of histone deacetylases (HDACs) in human cancer. Mol Oncol 1: 19–25.
[4]
Witt O, Deubzer HE, Milde T, Oehme I (2009) HDAC family: What are the cancer relevant targets? Cancer Lett 277: 8–21.
[5]
Rundlett SE, Carmen AA, Kobayashi R, Bavykin S, Turner BM, et al. (1996) HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proc Natl Acad Sci U S A 93: 14503–14508.
[6]
Rikimaru T, Taketomi A, Yamashita Y, Shirabe K, Hamatsu T, et al. (2007) Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma. Oncology 72: 69–74.
[7]
Keshelava N, Davicioni E, Wan Z, Ji L, Sposto R, et al. (2007) Histone deacetylase 1 gene expression and sensitization of multidrug-resistant neuroblastoma cell lines to cytotoxic agents by depsipeptide. J Natl Cancer Inst 99: 1107–1119.
[8]
Weichert W, Roske A, Gekeler V, Beckers T, Stephan C, et al. (2008) Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br J Cancer 98: 604–610.
[9]
Miyake K, Yoshizumi T, Imura S, Sugimoto K, Batmunkh E, et al. (2008) Expression of hypoxia-inducible factor-1alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma: correlation with poor prognosis with possible regulation. Pancreas 36: e1–9.
[10]
Senese S, Zaragoza K, Minardi S, Muradore I, Ronzoni S, et al. (2007) Role for histone deacetylase 1 in human tumor cell proliferation. Mol Cell Biol 27: 4784–4795.
[11]
Glaser KB, Li J, Staver MJ, Wei RQ, Albert DH, et al. (2003) Role of class I and class II histone deacetylases in carcinoma cells using siRNA. Biochem Biophys Res Commun 310: 529–536.
[12]
Nishioka C, Ikezoe T, Yang J, Takeuchi S, Koeffler HP, et al. (2008) MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk Res 32: 1382–1392.
[13]
Whetstine JR, Ceron J, Ladd B, Dufourcq P, Reinke V, et al. (2005) Regulation of Tissue-Specific and Extracellular Matrix-Related Genes by a Class I Histone Deacetylase. Molecular Cell 18: 483–490.
[14]
Kim NH, Kim S-N, Kim YK (2011) Involvement of HDAC1 in E-cadherin expression in prostate cancer cells; its implication for cell motility and invasion. Biochemical and Biophysical Research Communications 404: 915–921.
[15]
Oh M, Choi IK, Kwon HJ (2008) Inhibition of histone deacetylase1 induces autophagy. Biochem Biophys Res Commun 369: 1179–1183.
[16]
Noonan EJ, Place RF, Pookot D, Basak S, Whitson JM, et al. (2009) miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 28: 1714–1724.
[17]
Nam SW, Park JY, Ramasamy A, Shevade S, Islam A, et al. (2005) Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology 42: 809–818.
[18]
Sowa Y, Orita T, Minamikawa S, Nakano K, Mizuno T, et al. (1997) Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites. Biochem Biophys Res Commun 241: 142–150.
[19]
Huang L, Sowa Y, Sakai T, Pardee AB (2000) Activation of the p21WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites. Oncogene 19: 5712–5719.
[20]
Lagger G, Doetzlhofer A, Schuettengruber B, Haidweger E, Simboeck E, et al. (2003) The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene. Mol Cell Biol 23: 2669–2679.
[21]
Gui CY, Ngo L, Xu WS, Richon VM, Marks PA (2004) Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A 101: 1241–1246.
[22]
Noh JH, Jung KH, Kim JK, Eun JW, Bae HJ, et al. (2011) Aberrant Regulation of HDAC2 Mediates Proliferation of Hepatocellular Carcinoma Cells by Deregulating Expression of G1/S Cell Cycle Proteins. PLoS One 6: e28103.
[23]
Shao Y, Gao Z, Marks PA, Jiang X (2004) Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A 101: 18030–18035.
[24]
Yamamoto S, Tanaka K, Sakimura R, Okada T, Nakamura T, et al. (2008) Suberoylanilide hydroxamic acid (SAHA) induces apoptosis or autophagy-associated cell death in chondrosarcoma cell lines. Anticancer Res 28: 1585–1591.
[25]
Liu YL, Yang PM, Shun CT, Wu MS, Weng JR, et al. (2010) Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy 6: 1057–1065.
[26]
Scarlatti F, Bauvy C, Ventruti A, Sala G, Cluzeaud F, et al. (2004) Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 279: 18384–18391.
[27]
Glozak MA, Seto E (2007) Histone deacetylases and cancer. Oncogene 26: 5420–5432.
[28]
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, et al. (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1: 194–202.
[29]
Weichert W (2009) HDAC expression and clinical prognosis in human malignancies. Cancer Lett 280: 168–176.
[30]
Weichert W, Roske A, Niesporek S, Noske A, Buckendahl AC, et al. (2008) Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res 14: 1669–1677.
[31]
Wang GL, Salisbury E, Shi X, Timchenko L, Medrano EE, et al. (2008) HDAC1 promotes liver proliferation in young mice via interactions with C/EBPbeta. J Biol Chem 283: 26179–26187.
[32]
Wilting RH, Yanover E, Heideman MR, Jacobs H, Horner J, et al. Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis. EMBO J 29: 2586–2597.
[33]
Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, et al. (1998) Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391: 597–601.
[34]
Luo J, Su F, Chen D, Shiloh A, Gu W (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408: 377–381.
[35]
Yarden RI, Brody LC (1999) BRCA1 interacts with components of the histone deacetylase complex. Proc Natl Acad Sci U S A 96: 4983–4988.
[36]
Nakano K, Mizuno T, Sowa Y, Orita T, Yoshino T, et al. (1997) Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line. J Biol Chem 272: 22199–22206.
[37]
Niyazi M, Niyazi I, Belka C (2007) Counting colonies of clonogenic assays by using densitometric software. Radiat Oncol 2: 4.
