Abstract
As important regulators of chromatin, histone deacetylases (HDACs) are involved in silencing tumor suppressor genes. HDAC2, a member of HDACs, has been demonstrated to be implicated in the development and progression of various human malignancies; however, its expression and role in human primary gallbladder carcinoma (PGC) are not fully understood. Therefore, we conducted this study to address this problem. The subjects were 136 patients underwent resection for PGC. Immunostainings for HDAC2 were performed on these archival tissues. The correlation of HDAC2 expression with clinicopathological characteristics including survival was analyzed. HDAC2 was positively expressed in the nucleus of tumor cells in 86.0 % (117/136) of PGC but not in the normal epithelium of the gallbladder. Additionally, there was a significant difference in the incidence of positive nodal metastasis between high and low HDAC2 expression groups (P = 0.001). The incidences of advanced clinical stage (P = 0.005) and pathologic T stage (P < 0.001), and higher histologic grade (P < 0.001) were respectively higher in the high HDAC2 expression group than in the low group. Moreover, univariate and multivariate analyses revealed the high HDAC2 expression to be an independent prognostic factor for both overall and disease-free survival of patients with PGC. High HDAC2 expression was correlated with a high incidence of lymph node metastasis and aggressive tumor progression of PGC. It also was an independent prognostic factor for poorer overall and disease-free survival in patients. Therefore, detection of HDAC2 expression may help us screen patients at increased risk of malignant behavior for PGC.
Similar content being viewed by others
References
Misra S, Chaturvedi A, Misra NC, Sharma ID (2003) Carcinoma of the gallbladder. Lancet Oncol 4:167–176
Chen Y, Chen Y, Yu G, Ding H (2011) Lymphangiogenic and angiogentic microvessel density in gallbladder carcinoma. Hepatogastroenterology 58:20–25
Araida T, Higuchi R, Hamano M, Kodera Y, Takeshita N, Ota T, Yoshikawa T, Yamamoto M, Takasaki K (2009) Should the extrahepatic bile duct be resected or preserved in R0 radical surgery for advanced gallbladder carcinoma? results of a Japanese Society of Biliary Surgery Survey: a multicenter study. Surg Today 39:770–779
Kokudo N, Makuuchi M, Natori T, Sakamoto Y, Yamamoto J, Seki M, Noie T, Sugawara Y, Imamura H, Asahara S, Ikari T (2003) Strategies for surgical treatment of gallbladder carcinoma based on information available before resection. Arch Surg 138:741–750
Davies GF, Ross AR, Arnason TG, Juurlink BH, Harkness TA (2010) Troglitazone inhibits histone deacetylase activity in breast cancer cells. Cancer Lett 288:236–250
Brandl A, Heinzel T, Kramer OH (2009) Histone deacetylases: salesmen and customers in the post-translational modification market. Biol Cell Auspices Eur Cell Biol Organ 101:193–205
Ishdorj G, Graham BA, Hu X, Chen J, Johnston JB, Fang X, Gibson SB (2008) Lysophosphatidic acid protects cancer cells from histone deacetylase (HDAC) inhibitor-induced apoptosis through activation of HDAC. J Biol Chem 283:16818–16829
Mehdi O, Françoise S, Sofia CL, Urs G, Kevin Z, Bernard S, Igor S, Anabela CD, Dominique L, Eric M, Ali O (2012) HDAC gene expression in pancreatic tumor cell lines following treatment with the HDAC inhibitors panobinostat (LBH589) and trichostatine (TSA). Pancreatology 12:146–155
Spiegel S, Milstien S, Grant S (2012) Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene 31:537–551
Lee JH, Jeong EG, Choi MC, Kim SH, Park JH, Song SH, Park J, Bang YJ, Kim TY (2010) Inhibition of histone deacetylase 10 induces thioredoxin-interacting protein and causes accumulation of reactive oxygen species in SNU-620 human gastric cancer cells. Mol Cells 30:107–112
Xu LN, Wang X, Zou SQ (2008) Effect of histone deacetylase inhibitor on proliferation of biliary tract cancer cell lines. World J Gastroenterol 14:2578–2581
Yamaguchi J, Sasaki M, Sato Y, Itatsu K, Harada K, Zen Y, Ikeda H, Nimura Y, Nagino M, Nakanuma Y (2010) Histone deacetylase inhibitor (SAHA) and repression of EZH2 synergistically inhibit proliferation of gallbladder carcinoma. Cancer Sci 101:355–362
Kitamura T, Connolly K, Ruffino L, Ajiki T, Lueckgen A, Digiovanni J, Kiguchi K. (2012) The therapeutic effect of histone deacetylase inhibitor PCI-24781 on gallbladder carcinoma in BK5.erbB2 mice. J Hepatol. In press
Willis-Martinez D, Richards HW, Timchenko NA, Medrano EE (2010) Role of HDAC1 in senescence, aging, and cancer. Exp Gerontol 45:279–285
Schüler S, Fritsche P, Diersch S, Arlt A, Schmid RM, Saur D, Schneider G (2010) HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells. Mol Cancer 9:80
Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Xie HJ, Chang YG, Kim MG, Park H, Lee JY, Nam SW (2012) HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. J Cell Biochem 113:2167–2177
Patani N, Jiang WG, Newbold RF, Mokbel K (2011) Histone-modifier gene expression profiles are associated with pathological and clinical outcomes in human breast cancer. Anticancer Res 31:4115–4125
Quint K, Agaimy A, Di Fazio P, Montalbano R, Steindorf C, Jung R, Hellerbrand C, Hartmann A, Sitter H, Neureiter D, Ocker M (2011) Clinical significance of histone deacetylases 1, 2, 3, and 7: HDAC2 is an independent predictor of survival in HCC. Virchows Arch 459:129–139
Aghdassi A, Sendler M, Guenther A, Mayerle J, Behn CO, Heidecke CD, Friess H, Büchler M, Evert M, Lerch MM, Weiss FU (2012) Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. Gut 61:439–448
Ramsey MR, He L, Forster N, Ory B, Ellisen LW (2011) Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma. Cancer Res 71:4373–4379
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749
Khier H, Bartl S, Schuettengruber B, Seiser C (1999) Molecular cloning and characterization of the mouse histone deacetylase 1 gene: integration of a retrovirus in 129SV mice. Biochim Biophys Acta 1489:365–373
Brunmeir R, Lagger S, Seiser C (2009) Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. Int J Dev Biol 53:275–289
Yamaguchi T, Cubizolles F, Zhang Y, Reichert N, Kohler H, Seiser C, Matthias P (2010) Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev 24:455–469
Jurkin J, Zupkovitz G, Lagger S, Grausenburger R, Hagelkruys A, Kenner L, Seiser C (2011) Distinct and redundant functions of histone deacetylases HDAC1 and HDAC2 in proliferation and tumorigenesis. Cell Cycle 10:406–412
Huang BH, Laban M, Leung CH, Lee L, Lee CK, Salto-Tellez M, Raju GC, Hooi SC (2005) Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ 12:395–404
Harms KL, Chen X (2007) Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res 67:3145–3152
Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Göttlicher M (2004) Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5:455–463
Chang HH, Chiang CP, Hung HC, Lin CY, Deng YT, Kuo MY (2009) Histone deacetylase 2 expression predicts poorer prognosis in oral cancer patients. Oral Oncol 45:610–614
Conflict of interest statement
None.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Source of support
This work was supported by the National Natural Science Foundation of China (no.81172287)
Xilin Du and Huadong Zhao equally contribute to this work.
Rights and permissions
About this article
Cite this article
Du, X., Zhao, H., Zang, L. et al. Overexpression of Histone Deacetylase 2 Predicts Unfavorable Prognosis in Human Gallbladder Carcinoma. Pathol. Oncol. Res. 19, 397–403 (2013). https://doi.org/10.1007/s12253-012-9592-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-012-9592-y