Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma

Ahn,Mee-Young; Yoon,Jung-Hoon

doi:10.3892/or.2016.5280

Histone deacetylase 8 as a novel therapeutic target in oral squamous cell carcinoma

Authors:
- Mee-Young Ahn
- Jung-Hoon Yoon
View Affiliations

Affiliations: College of Medical and Life Sciences, Division of Bio-industry, Major in Pharmaceutical Engineering, Silla University, Busan 46958, Republic of Korea, Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang Bone Regeneration Research Institute, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, Republic of Korea
Published online on: November 29, 2016 https://doi.org/10.3892/or.2016.5280
Pages: 540-546

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The overexpression of histone deacetylases (HDACs) has been observed in many cancers and inhibition of specific HDAC has emerged as a new target for cancer therapy. The present study examined the expression of HDAC8 and the inhibitory effect of HDAC8 in oral squamous cell carcinoma (OSCC). The expression of HDAC8 was measured in human OSCC tissues and OSCC cell lines using immunohistochemistry and immunoblotting. HDAC8 was knocked down in OSCC cells by transfection with HDAC8 siRNAs and cell proliferation was quantified. Apoptosis and autophagy were measured using flow cytometry and immunoblotting. HDAC8 were overexpressed in OSCC tissues and OSCC cells, mainly localized in the cytoplasm. HDAC8 siRNAs effectively reduced the level of HDAC8 expression and HDAC8 silencing significantly inhibited the proliferation of OSCC cells. HDAC8 knockdown induced apoptotic cell death through caspases activation and pro-survival autophagy in OSCC cells. Combination with HDAC silencing and autophagy inhibition enhanced cell death by increasing apoptosis in OSCC cells. This study suggests that inhibition of HDAC8 might become a novel therapeutic strategy for OSCC.

View Figures

View References

1	Effiom OA, Adeyemo WL, Omitola OG, Ajayi OF, Emmanuel MM and Gbotolorun OM: Oral squamous cell carcinoma: a clinicopathologic review of 233 cases in Lagos, Nigeria. J Oral Maxillofac Surg. 66:1595–1599. 2008. View Article : Google Scholar : PubMed/NCBI
2	Zushi Y, Narisawa-Saito M, Noguchi K, Yoshimatsu Y, Yugawa T, Egawa N, Fujita M, Urade M and Kiyono T: An in vitro multistep carcinogenesis model for both HPV-positive and -negative human oral squamous cell carcinomas. Am J Cancer Res. 1:869–881. 2011.PubMed/NCBI
3	Weng CJ, Hsieh YH, Chen MK, Tsai CM, Lin CW and Yang SF: Survivin SNP-carcinogen interactions in oral cancer. J Dent Res. 91:358–363. 2012. View Article : Google Scholar : PubMed/NCBI
4	Mascolo M, Siano M, Ilardi G, Russo D, Merolla F, De Rosa G and Staibano S: Epigenetic disregulation in oral cancer. Int J Mol Sci. 13:2331–2353. 2012. View Article : Google Scholar : PubMed/NCBI
5	Mydlarz WK, Hennessey PT and Califano JA: Advances and perspectives in the molecular diagnosis of head and neck cancer. Expert Opin Med Diagn. 4:53–65. 2010. View Article : Google Scholar : PubMed/NCBI
6	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar : PubMed/NCBI
7	Chen YJ, Chang JT, Liao CT, Wang HM, Yen TC, Chiu CC, Lu YC, Li HF and Cheng AJ: Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci. 99:1507–1514. 2008. View Article : Google Scholar : PubMed/NCBI
8	Agrawal D, Gupta S, Agarwal D, Gupta OP and Agarwal M: Role of GSTM1 and GSTT1 polymorphism: susceptibility to oral submucous fibrosis in the North Indian population. Oncology. 79:181–186. 2010. View Article : Google Scholar : PubMed/NCBI
9	Marks PA and Dokmanovic M: Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin Investig Drugs. 14:1497–1511. 2005. View Article : Google Scholar : PubMed/NCBI
10	Delcuve GP, Khan DH and Davie JR: Targeting class I histone deacetylases in cancer therapy. Expert Opin Ther Targets. 17:29–41. 2013. View Article : Google Scholar : PubMed/NCBI
11	Lucio-Eterovic AK, Cortez MA, Valera ET, Motta FJ, Queiroz RG, Machado HR, et al: Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas. BMC Cancer. 8:243–253. 2008. View Article : Google Scholar : PubMed/NCBI
12	Martin M, Kettmann R and Dequiedt F: Class IIa histone deacetylases: regulating the regulators. Oncogene. 26:5450–5467. 2007. View Article : Google Scholar : PubMed/NCBI
13	Weichert W, Denkert C, Noske A, Darb-Esfahani S, Dietel M, Kalloger SE, Huntsman DG and Köbel M: Expression of Class I histone deacetylases indicates poor prognosis in endometrioid subtypes of ovarian and endometrial carcinomas. Neoplasia. 10:1021–1027. 2008. View Article : Google Scholar : PubMed/NCBI
14	Iglesias-Linares A, Yañez-Vico RM and González-Moles MA: Potential role of HDAC inhibitors in cancer therapy: insights into oral squamous cell carcinoma. Oral Oncol. 46:323–329. 2010. View Article : Google Scholar : PubMed/NCBI
15	Chang HH, Chiang CP, Hung HC, Lin CY, Deng YT and Kuo MY: Histone deacetylase 2 expression predicts poorer prognosis in oral cancer patients. Oral Oncol. 45:610–614. 2009. View Article : Google Scholar : PubMed/NCBI
16	Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B, Kopp-Schneider A, Westermann F, Ulrich SM, von Deimling A, et al: Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res. 15:91–99. 2009. View Article : Google Scholar : PubMed/NCBI
17	Kim SA, Kwon SM, Yoon JH and Ahn SG: The antitumor effect of PLK1 and HSF1 double knockdown on human oral carcinoma cells. Int J Oncol. 36:867–872. 2010.PubMed/NCBI
18	Kanematsu S, Uehara N, Miki H, Yoshizawa K, Kawanaka A, Yuri T and Tsubura A: Autophagy inhibition enhances sulforaphane-induced apoptosis in human breast cancer cells. Anticancer Res. 30:3381–3390. 2010.PubMed/NCBI
19	Shakespear MR, Halili MA, Irvine KM, Fairlie DP and Sweet MJ: Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 32:335–343. 2011. View Article : Google Scholar : PubMed/NCBI
20	Lehmann M, Hoffmann MJ, Koch A, Ulrich SM, Schulz WA and Niegisch G: Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment. J Exp Clin Cancer Res. 10:592014. View Article : Google Scholar
21	Lopez G, Bill KL, Bid HK, Braggio D, Constantino D, Prudner B, Zewdu A, Batte K, Lev D and Pollock RE: HDAC8, a potential therapeutic target for the treatment of malignant peripheral nerve sheath tumors (MPNST). PLoS One. 10:e01333022015. View Article : Google Scholar : PubMed/NCBI
22	Nakagawa M, Oda Y, Eguchi T, Aishima S, Yao T, Hosoi F, Basaki Y, Ono M, Kuwano M, Tanaka M, et al: Expression profile of class I histone deacetylases in human cancer tissues. Oncol Rep. 18:769–774. 2007.PubMed/NCBI
23	Niegisch G, Knievel J, Koch A, Hader C, Fischer U, Albers P and Schulz WA: Changes in histone deacetylase (HDAC) expression patterns and activity of HDAC inhibitors in urothelial cancers. Urol Oncol. 31:1770–1779. 2013. View Article : Google Scholar : PubMed/NCBI
24	Kim HJ and Bae SC: Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res. 3:166–179. 2011.PubMed/NCBI
25	Gray SG and Ekstrom TJ: The human histone deacetylase family. Exp Cell Res. 262:75–83. 2001. View Article : Google Scholar : PubMed/NCBI
26	de Ruijter AJ, van Gennip AH, Caron HN, Kemp S and van Kuilenburg AB: Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 370:737–749. 2003. View Article : Google Scholar : PubMed/NCBI
27	Gregoretti IV, Lee YM and Goodson HV: Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol. 338:17–31. 2004. View Article : Google Scholar : PubMed/NCBI
28	Oehme I, Deubzer HE, Lodrini M, Milde T and Witt O: Targeting of HDAC8 and investigational inhibitors in neuroblastoma. Expert Opin Investig Drugs. 18:1605–1617. 2009. View Article : Google Scholar : PubMed/NCBI
29	Waltregny D, De Leval L, Glénisson W, Ly Tran S, North BJ, Bellahcène A, Weidle U, Verdin E and Castronovo V: Expression of histone deacetylase 8, a class I histone deacetylase, is restricted to cells showing smooth muscle differentiation in normal human tissues. Am J Pathol. 165:553–564. 2004. View Article : Google Scholar : PubMed/NCBI
30	Waltregny D, North B, Van Mellaert F, de Leval J, Verdin E and Castronovo V: Screening of histone deacetylases (HDAC) expression in human prostate cancer reveals distinct class I HDAC profiles between epithelial and stromal cells. Eur J Histochem. 48:273–290. 2004.PubMed/NCBI
31	Mathias RA, Guise AJ and Cristea IM: Post-translational modifications regulate class IIa histone deacetylase (HDAC) function in health and disease. Mol Cell Proteomics. 14:456–470. 2015. View Article : Google Scholar : PubMed/NCBI
32	Quan P, Moinfar F, Kufferath I, Absenger M, Kueznik T, Denk H, Zatloukal K and Haybaeck J: Effects of targeting endometrial stromal sarcoma cells via histone deacetylase and PI3K/AKT/mTOR signaling. Anticancer Res. 34:2883–2897. 2014.PubMed/NCBI
33	Wu J, Du C, Lv Z, Ding C, Cheng J, Xie H, Zhou L and Zheng S: The up-regulation of histone deacetylase 8 promotes proliferation and inhibits apoptosis in hepatocellular carcinoma. Dig Dis Sci. 58:3545–3553. 2013. View Article : Google Scholar : PubMed/NCBI
34	Liu JJ, Lin M, Yu JY, Liu B and Bao JK: Targeting apoptotic and autophagic pathways for cancer therapeutics. Cancer Lett. 300:105–114. 2011. View Article : Google Scholar : PubMed/NCBI
35	Hannigan AM and Gorski SM: Macroautophagy: the key ingredient to a healthy diet? Autophagy. 5:140–151. 2009. View Article : Google Scholar : PubMed/NCBI
36	Zhang Q, Yang W, Man N, Zheng F, Shen Y, Sun K, Li Y and Wen LP: Autophagy-mediated chemosensitization in cancer cells by fullerene C60 nanocrystal. Autophagy. 5:1107–1117. 2009. View Article : Google Scholar : PubMed/NCBI
37	Levine B: Cell biology: Autophagy and cancer. Nature. 446:745–747. 2007. View Article : Google Scholar : PubMed/NCBI
38	Kondo Y, Kanzawa T, Sawaya R and Kondo S: The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 5:726–734. 2005. View Article : Google Scholar : PubMed/NCBI
39	Jin SK and White E: Tumor suppression by autophagy through the management of metabolic stress. Autophagy. 4:563–566. 2008. View Article : Google Scholar : PubMed/NCBI
40	Lee JY and Yao TP: Quality control autophagy: a joint effort of ubiquitin, protein deacetylase and actin cytoskeleton. Autophagy. 6:555–557. 2010. View Article : Google Scholar : PubMed/NCBI
41	Park JY and Juhnn YS: cAMP signaling increases histone deacetylase 8 expression by inhibiting JNK-dependent degradation via autophagy and the proteasome system in H1299 lung cancer cells. Biochem Biophys Res Commun. 470:336–342. 2016. View Article : Google Scholar : PubMed/NCBI
42	Ahn MY, Ahn SG and Yoon JH: Apicidin, a histone deaceylase inhibitor, induces both apoptosis and autophagy in human oral squamous carcinoma cells. Oral Oncol. 47:1032–1038. 2011. View Article : Google Scholar : PubMed/NCBI