Overexpression of HDAC6 suppresses tumor cell proliferation and metastasis by inhibition of the canonical Wnt/β‑catenin signaling pathway in hepatocellular carcinoma

Yin,Zhusheng; Xu,Wei; Xu,Hao; Zheng,Junnian; Gu,Yuming

doi:10.3892/ol.2018.9504

Overexpression of HDAC6 suppresses tumor cell proliferation and metastasis by inhibition of the canonical Wnt/β‑catenin signaling pathway in hepatocellular carcinoma

Authors:
- Zhusheng Yin
- Wei Xu
- Hao Xu
- Junnian Zheng
- Yuming Gu
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Affiliations: Department of Interventional Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China, Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China
Published online on: September 26, 2018 https://doi.org/10.3892/ol.2018.9504
Pages: 7082-7090
Copyright: © Yin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Histone deacetylase 6 (HDAC6), a specific histone deacetylase family member, serves an essential role in the regulation of gene expression, cell cycle progression, autophagy and apoptosis. There are numerous reports on the function of HDAC6 in cancer. However, the specific function of HDAC6 in hepatocellular carcinoma (HCC) has yet to be revealed. In the present study, the expression of HDAC6 was revealed to be downregulated in human HCC cell lines and tissues. The aberrant activation of the canonical Wnt/β‑catenin signaling pathway was revealed to be involved in hepatocarcinogenesis and metastasis. It was additionally revealed that the overexpression of HDAC6 decreased the expression of β‑catenin protein levels which attenuated the canonical Wnt/β‑catenin signaling pathway and suppressed the proliferation of HCC cells. In addition, the upregulation of HDAC6 inhibited the epithelial‑to‑mesenchymal transition in HCC by increasing the E‑cadherin protein levels and decreasing the N‑cadherin, vimentin and matrix metalloproteinase‑9 protein levels. Furthermore, HDAC6 also exerted an effect on the cell cycle arrest and the induction of apoptosis. These results demonstrated that HDAC6 functioned as a tumor suppressor in HCC by attenuating the activity of the canonical Wnt/β‑catenin signaling pathway. Therefore, HDAC6 may serve as a potential therapeutic target for the treatment of HCC.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
3	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
4	Marks P, Rifkind RA, Richon VM, Breslow R, Miller T and Kelly WK: Histone deacetylases and cancer: Causes and therapies. Nat Rev Cancer. 1:194–202. 2001. View Article : Google Scholar : PubMed/NCBI
5	Seidel C, Schnekenburger M, Dicato M and Diederich M: Histone deacetylase 6 in health and disease. Epigenomics. 7:103–118. 2015. View Article : Google Scholar : PubMed/NCBI
6	Valenzuela-Fernández A, Cabrero JR, Serrador JM and Sánchez-Madrid F: HDAC6: A key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol. 18:291–297. 2008. View Article : Google Scholar : PubMed/NCBI
7	Zheng Q and Wang X: Autophagy and the ubiquitin-proteasome system in cardiac dysfunction. Panminerva Med. 52:9–25. 2010.PubMed/NCBI
8	Aldana-Masangkay GI and Sakamoto KM: The role of HDAC6 in cancer. J Biomed Biotechnol. 2011:8758242011. View Article : Google Scholar : PubMed/NCBI
9	Bienz M and Clevers H: Linking colorectal cancer to Wnt signaling. Cell. 103:311–320. 2000. View Article : Google Scholar : PubMed/NCBI
10	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
11	Chen C, Xue Y, Zhang D, Xu W, Xu H, Yao H, Pei D and Gu Y: Short hairpin RNA silencing of TGF-βRII and FZD-7 synergistically suppresses proliferation and metastasis of hepatocellular carcinoma cells. Oncol Lett. 11:2039–2046. 2016. View Article : Google Scholar : PubMed/NCBI
12	Tian Y, Mok MT, Yang P and Cheng AS: Epigenetic activation of Wnt/β-catenin signaling in NAFLD-associated hepatocarcinogenesis. Cancers (Basel). 8:E762016. View Article : Google Scholar : PubMed/NCBI
13	Nelson WJ and Nusse R: Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 303:1483–1487. 2004. View Article : Google Scholar : PubMed/NCBI
14	Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X and He X: Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 108:837–847. 2002. View Article : Google Scholar : PubMed/NCBI
15	Ikeda S, Kishida S, Yamamoto H, Murai H, Koyama S and Kikuchi A: Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J. 17:1371–1384. 1998. View Article : Google Scholar : PubMed/NCBI
16	Zhu J, Coyne CB and Sarkar SN: PKC alpha regulates Sendai virus-mediated interferon induction through HDAC6 and β-catenin. EMBO J. 30:4838–4849. 2011. View Article : Google Scholar : PubMed/NCBI
17	Ding G, Liu HD, Huang Q, Liang HX, Ding ZH, Liao ZJ and Huang G: HDAC6 promotes hepatocellular carcinoma progression by inhibiting P53 transcriptional activity. FEBS Lett. 587:880–886. 2013. View Article : Google Scholar : PubMed/NCBI
18	Kanno K, Kanno S, Nitta H, Uesugi N, Sugai T, Masuda T, Wakabayashi G and Maesawa C: Overexpression of histone deacetylase 6 contributes to accelerated migration and invasion activity of hepatocellular carcinoma cells. Oncol Rep. 28:867–873. 2012. View Article : Google Scholar : PubMed/NCBI
19	Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Chang YG, Kim MG, Park WS, Lee JY, Lee SY, et al: Histone deacetylase 6 functions as a tumor suppressor by activating c-Jun NH2-terminal kinase-mediated beclin 1-dependent autophagic cell death in liver cancer. Hepatology. 56:644–657. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bae HJ, Jung KH, Eun JW, Shen Q, Kim HS, Park SJ, Shin WC, Yang HD, Park WS, Lee JY and Nam SW: MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. J Hepatol. 63:408–419. 2015. View Article : Google Scholar : PubMed/NCBI
21	Lv Z, Weng X, Du C, Zhang C, Xiao H, Cai X, Ye S, Cheng J, Ding C, Xie H, et al: Downregulation of HDAC6 promotes angiogenesis in hepatocellular carcinoma cells and predicts poor prognosis in liver transplantation patients. Mol Carcinog. 55:1024–1033. 2016. View Article : Google Scholar : PubMed/NCBI
22	Reya T and Clevers H: Wnt signalling in stem cells and cancer. Nature. 434:843–850. 2005. View Article : Google Scholar : PubMed/NCBI
23	Li Y, Zhang X, Polakiewicz RD, Yao TP and Comb MJ: HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization. J Biol Chem. 283:12686–12690. 2008. View Article : Google Scholar : PubMed/NCBI
24	Mak AB, Nixon AM, Kittanakom S, Stewart JM, Chen GI, Curak J, Gingras AC, Mazitschek R, Neel BG, Stagljar I and Moffat J: Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation. Cell Rep. 2:951–963. 2012. View Article : Google Scholar : PubMed/NCBI
25	Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S, Larin A, Savchenko V, Francis GL, de la Chapelle A, et al: Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci USA. 104:2803–2088. 2007. View Article : Google Scholar : PubMed/NCBI
26	Todaro M, Iovino F, Eterno V, Cammareri P, Gambara G, Espina V, Gulotta G, Dieli F, Giordano S, De Maria R and Stassi G: Tumorigenic and metastatic activity of human thyroid cancer stem cells. Cancer Res. 70:8874–8885. 2010. View Article : Google Scholar : PubMed/NCBI
27	Salminen A, Kauppinen A and Kaarniranta K: AMPK/Snf1 signaling regulates histone acetylation: Impact on gene expression and epigenetic functions. Cell Signal. 28:887–895. 2016. View Article : Google Scholar : PubMed/NCBI
28	Park G, Tan J, Garcia G, Kang Y, Salvesen G and Zhang Z: Regulation of histone acetylation by autophagy in Parkinson disease. J Biol Chem. 291:3531–3540. 2016. View Article : Google Scholar : PubMed/NCBI
29	Witt O, Deubzer HE, Milde T and Oehme I: HDAC family: What are the cancer relevant targets? Cancer Lett. 277:8–21. 2009. View Article : Google Scholar : PubMed/NCBI
30	Lee JY, Kuo CW, Tsai SL, Cheng SM, Chen SH, Chan HH, Lin CH, Lin KY, Li CF, Kanwar JR, et al: Inhibition of HDAC3- and HDAC6-promoted survivin expression plays an important role in SAHA-induced autophagy and viability reduction in breast cancer cells. Front Pharmacol. 7:812016. View Article : Google Scholar : PubMed/NCBI
31	Lim JA and Juhnn YS: Isoproterenol increases histone deacetylase 6 expression and cell migration by inhibiting ERK signaling via PKA and Epac pathways in human lung cancer cells. Exp Mol Med. 48:e2042016. View Article : Google Scholar : PubMed/NCBI
32	Hackanson B, Rimmele L, Benkißer M, Abdelkarim M, Fliegauf M, Jung M and Lübbert M: HDAC6 as a target for antileukemic drugs in acute myeloid leukemia. Leuk Res. 36:1055–1062. 2012. View Article : Google Scholar : PubMed/NCBI
33	Wang SH, Li N, Wei Y, Li QR and Yu ZP: β-catenin deacetylation is essential for WNT-induced proliferation of breast cancer cells. Mol Med Rep. 9:973–978. 2014. View Article : Google Scholar : PubMed/NCBI
34	Ye Y, Long X, Zhang L, Chen J, Liu P, Li H, Wei F, Yu W, Ren X and Yu J: NTS/NTR1 co-expression enhances epithelial-to-mesenchymal transition and promotes tumor metastasis by activating the Wnt/β-catenin signaling pathway in hepatocellular carcinoma. Oncotarget. 7:70303–70322. 2016. View Article : Google Scholar : PubMed/NCBI
35	Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, Huang DD, Tang L, Kong XN, et al: Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 68:4287–4295. 2008. View Article : Google Scholar : PubMed/NCBI
36	Yuan Z, Yu X, Ni B, Chen D, Yang Z, Huang J, Wang J, Chen D and Wang L: Overexpression of long non-coding RNA-CTD903 inhibits colorectal cancer invasion and migration by repressing Wnt/β-catenin signaling and predicts favorable prognosis. Int J Oncol. 48:2675–2685. 2016. View Article : Google Scholar : PubMed/NCBI
37	Baldwin LA, Hoff JT, Lefringhouse J, Zhang M, Jia C, Liu Z, Erfani S, Jin H, Xu M, She QB, et al: CD151-α3β1 integrin complexes suppress ovarian tumor growth by repressing slug-mediated EMT and canonical Wnt signaling. Oncotarget. 5:12203–12217. 2014. View Article : Google Scholar : PubMed/NCBI
38	Zou W, Zou Y, Zhao Z, Li B and Ran P: Nicotine-induced epithelial-mesenchymal transition via Wnt/β-catenin signaling in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 304:L199–L209. 2013. View Article : Google Scholar : PubMed/NCBI
39	Liu CC, Cai DL, Sun F, Wu ZH, Yue B, Zhao SL, Wu XS, Zhang M, Zhu XW, Peng ZH and Yan DW: FERMT1 mediates epithelial-mesenchymal transition to promote colon cancer metastasis via modulation of β-catenin transcriptional activity. Oncogene. 36:1779–1792. 2017. View Article : Google Scholar : PubMed/NCBI
40	Liu ZJ, Liu HL, Zhou HC and Wang GC: TIPE2 inhibits hypoxia-induced Wnt/β-catenin pathway activation and EMT in glioma cells. Oncol Res. 24:255–261. 2016. View Article : Google Scholar : PubMed/NCBI