Overexpression of histone deacetylase 6 contributes to accelerated migration and invasion activity of hepatocellular carcinoma cells

Kanno,Kiminori; Kanno,Shoji; Nitta,Hiroyuki; Uesugi,Noriyuki; Sugai,Tamostu; Masuda,Tomoyuki; Wakabayashi,Go; Maesawa,Chihaya

doi:10.3892/or.2012.1898

Overexpression of histone deacetylase 6 contributes to accelerated migration and invasion activity of hepatocellular carcinoma cells

Authors:
- Kiminori Kanno
- Shoji Kanno
- Hiroyuki Nitta
- Noriyuki Uesugi
- Tamostu Sugai
- Tomoyuki Masuda
- Go Wakabayashi
- Chihaya Maesawa
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Affiliations: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Morioka, Japan, Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan, Division of Diagnostic Molecular Pathology, Department of Pathology, School of Medicine, Iwate Medical University, Morioka, Japan, Department of Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
Published online on: July 4, 2012 https://doi.org/10.3892/or.2012.1898
Pages: 867-873

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Abstract

Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that regulates many important biological processes, including cell migration, viral infection and autophagy. The aim of this study was to investigate the significance of HDAC6 in the invasion and metastasis activities of hepatocellular carcinoma (HCC). Three HCC cell lines and two primary cultures of hepatocytes were used for biological experiments. Immunohistochemistry for HDAC6 protein was also examined in 70 resected primary HCCs. Knockdown of the HDAC6 gene in the HCC cell lines was carried out by treatment with siRNA, and their migration and invasion activities were examined by the scratch assay and Matrigel invasion assay, respectively. HDAC6 expression was greater in all of the HCC cell lines compared to the primary cultures of hepatocytes. Knockdown of HDAC6 markedly downregulated the migration and invasion activities of all HCC cell lines (P<0.05). Overexpression of HDAC6 protein to a level higher than that in the corresponding normal hepatocytes was observed in 14 (20%) of the 70 primary HCCs, and was significantly correlated with high clinical stage, number of tumors, vascular invasion and intrahepatic metastasis (P<0.05). These results suggest that overexpression of the HDAC6 protein is involved in the migration and invasion activities of HCC cells, and may be a good biomarker for prediction of intrahepatic metastasis.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar
2	Takahara T, Nitta H, Hasegawa Y, Itou N, Takahashi M and Wakabayashi G: Using sorafenib for recurrent hepatocellular carcinoma after liver transplantation - interactions between calcineurin inhibitor: two case reports. Transplant Proc. 43:2800–2805. 2011. View Article : Google Scholar
3	Nitta H, Sasaki A, Fujita T, et al: Laparoscopy-assisted major liver resections employing a hanging technique: the original procedure. Ann Surg. 251:450–453. 2010. View Article : Google Scholar : PubMed/NCBI
4	Sasaki A, Nitta H, Otsuka K, Takahara T, Nishizuka S and Wakabayashi G: Ten-year experience of totally laparoscopic liver resection in a single institution. Br J Surg. 96:274–279. 2009.PubMed/NCBI
5	Llovet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet. 362:1907–1917. 2003. View Article : Google Scholar
6	Salhab M and Canelo R: An overview of evidence-based management of hepatocellular carcinoma: a meta-analysis. J Cancer Res Ther. 7:463–475. 2011. View Article : Google Scholar : PubMed/NCBI
7	Thomas MB, Jaffe D, Choti MM, et al: Hepatocellular carcinoma: consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol. 28:3994–4005. 2010. View Article : Google Scholar
8	Izumi N, Asahina Y, Noguchi O, et al: Risk factors for distant recurrence of hepatocellular carcinoma in the liver after complete coagulation by microwave or radiofrequency ablation. Cancer. 91:949–956. 2001. View Article : Google Scholar : PubMed/NCBI
9	Poon RT, Fan ST, Ng IO, Lo CM, Liu CL and Wong J: Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer. 89:500–507. 2000. View Article : Google Scholar : PubMed/NCBI
10	Arii S, Monden K, Niwano M, et al: Results of surgical treatment for recurrent hepatocellular carcinoma; comparison of outcome among patients with multicentric carcinogenesis, intrahepatic metastasis, and extrahepatic recurrence. J Hepatobiliary Pancreat Surg. 5:86–92. 1998. View Article : Google Scholar
11	Miyata R, Tanimoto A, Wakabayashi G, et al: Accuracy of preoperative prediction of microinvasion of portal vein in hepatocellular carcinoma using superparamagnetic iron oxide-enhanced magnetic resonance imaging and computed tomography during hepatic angiography. J Gastroenterol. 41:987–995. 2006. View Article : Google Scholar
12	Ma WL, Hsu CL, Yeh CC, et al: Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology. Feb 9–2012.(Epub ahead of print).
13	Yamazaki K, Masugi Y and Sakamoto M: Molecular pathogenesis of hepatocellular carcinoma: altering transforming growth factor-beta signaling in hepatocarcinogenesis. Dig Dis. 29:284–288. 2011. View Article : Google Scholar
14	Zheng F, Liao YJ, Cai MY, et al: The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 61:278–289. 2012. View Article : Google Scholar : PubMed/NCBI
15	Fu J, Chen Y, Cao J, et al: p28(GANK) overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1alpha pathways. Hepatology. 53:181–192. 2012. View Article : Google Scholar
16	Yao J, Liang L, Huang S, et al: MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma. Hepatology. 51:846–856. 2010.PubMed/NCBI
17	Mazzocca A, Liotta F and Carloni V: Tetraspanin CD81-regulated cell motility plays a critical role in intrahepatic metastasis of hepatocellular carcinoma. Gastroenterology. 135:244–256. 2008. View Article : Google Scholar : PubMed/NCBI
18	Sakon M, Nagano H, Nakamori S, et al: Intrahepatic recurrences of hepatocellular carcinoma after hepatectomy: analysis based on tumor hemodynamics. Arch Surg. 137:94–99. 2002. View Article : Google Scholar : PubMed/NCBI
19	Gundersen GG and Bulinski JC: Selective stabilization of microtubules oriented toward the direction of cell migration. Proc Natl Acad Sci USA. 85:5946–5950. 1988. View Article : Google Scholar : PubMed/NCBI
20	Hubbert C, Guardiola A, Shao R, et al: HDAC6 is a microtubule-associated deacetylase. Nature. 417:455–458. 2002. View Article : Google Scholar : PubMed/NCBI
21	Tran AD, Marmo TP, Salam AA, et al: HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J Cell Sci. 120:1469–1479. 2007. View Article : Google Scholar : PubMed/NCBI
22	Wu H and Parsons JT: Cortactin, an 80/85-kilodalton pp60src substrate, is a filamentous actin-binding protein enriched in the cell cortex. J Cell Biol. 120:1417–1426. 1993. View Article : Google Scholar : PubMed/NCBI
23	Luxton GW and Gundersen GG: HDAC6-pack: cortactin acetylation joins the brew. Dev Cell. 13:161–162. 2007. View Article : Google Scholar : PubMed/NCBI
24	Tsunoda K, Oikawa H, Tada H, et al: Nucleus accumbens-associated 1 contributes to cortactin deacetylation and augments the migration of melanoma cells. J Invest Dermatol. 131:1710–1719. 2011. View Article : Google Scholar : PubMed/NCBI
25	Zuo Q, Wu W, Li X, Zhao L and Chen W: HDAC6 and SIRT2 promote bladder cancer cell migration and invasion by targeting cortactin. Oncol Rep. 27:819–824. 2012.PubMed/NCBI
26	Park SY, Jun JA, Jeong KJ, et al: Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer. Oncol Rep. 25:1677–1681. 2011.PubMed/NCBI
27	Joshi A and Cao D: TGF-beta signaling, tumor microenvironment and tumor progression: the butterfly effect. Front Biosci. 15:180–194. 2010. View Article : Google Scholar : PubMed/NCBI
28	Yu J, Ustach C and Kim HR: Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol. 36:49–59. 2003. View Article : Google Scholar : PubMed/NCBI
29	Lu X and Kang Y: Epidermal growth factor signalling and bone metastasis. Br J Cancer. 102:457–461. 2010. View Article : Google Scholar : PubMed/NCBI
30	Zhou HY, Pon YL and Wong AS: HGF/MET signaling in ovarian cancer. Curr Mol Med. 8:469–480. 2008. View Article : Google Scholar : PubMed/NCBI
31	Yang JD, Nakamura I and Roberts LR: The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 21:35–43. 2011. View Article : Google Scholar : PubMed/NCBI
32	Yang XR, Xu Y, Yu B, et al: CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clin Cancer Res. 15:5518–5527. 2009. View Article : Google Scholar : PubMed/NCBI
33	Inayoshi J, Ichida T, Sugitani S, et al: Gross appearance of hepatocellular carcinoma reflects E-cadherin expression and risk of early recurrence after surgical treatment. J Gastroenterol Hepatol. 18:673–677. 2003. View Article : Google Scholar
34	Wong CC, Wong CM, Tung EK, Man K and Ng IO: Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion. Hepatology. 49:1583–1594. 2009. View Article : Google Scholar : PubMed/NCBI
35	Yokomizo C, Yamaguchi K, Itoh Y, et al: High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells. Cancer Lett. 310:140–147. 2011. View Article : Google Scholar : PubMed/NCBI
36	Miyoshi A, Kitajima Y, Kido S, et al: Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma. Br J Cancer. 92:252–258. 2005.PubMed/NCBI
37	Aldana-Masangkay GI and Sakamoto KM: The role of HDAC6 in cancer. J Biomed Biotechnol. 2011:8758242011. View Article : Google Scholar : PubMed/NCBI
38	Grozinger CM, Hassig CA and Schreiber SL: Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc Natl Acad Sci USA. 96:4868–4873. 1999. View Article : Google Scholar : PubMed/NCBI
39	Haggarty SJ, Koeller KM, Wong JC, Grozinger CM and Schreiber SL: Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA. 100:4389–4394. 2003. View Article : Google Scholar : PubMed/NCBI
40	Haggarty SJ, Koeller KM, Wong JC, Butcher RA and Schreiber SL: Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays. Chem Biol. 10:383–396. 2003. View Article : Google Scholar
41	Bazzaro M, Lin Z, Santillan A, et al: Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor. Clin Cancer Res. 14:7340–7347. 2008. View Article : Google Scholar : PubMed/NCBI
42	Santo L, Hideshima T, Kung AL, et al: Preclinical activity, pharmacodynamic and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 119:2579–2589. 2012. View Article : Google Scholar : PubMed/NCBI
43	Kim HS, Vassilopoulos A, Wang RH, et al: SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell. 20:487–499. 2011. View Article : Google Scholar : PubMed/NCBI