Purpose: Sirtuins (SIRTs) are the family of proteins associated with the cell cycle and that correlate with cancer development and progression. SIRTs have never been studied in uveal melanocytes. The aim of this study is to characterize the expression of SIRT2 in uveal melanoma (UM) cases and compare it with the expression of SIRT2 in melanocytes of the uveal tract of normal human eyes (NHE). Methods: Twenty-one formalin-fixed, paraffin-embedded human UM cases were immunostained for SIRT2, along with 15 NHE obtained from the Eye Bank of Canada. Results: SIRT2 expression was higher in melanomas than in normal melanocytes of both tumor and donor eyes (p < 0.0001). No significant difference in SIRT2 expression was found when comparing normal melanocytes in UM and NHE cases. Conclusions: SIRT2 expression is significantly stronger in UM cells than in normal ocular melanocytes. This finding may indicate an important role of SIRT2 as a prognostic marker in UM progression. SIRT2 should also be investigated as a possible therapeutic target.

1.
Schilling B, Schneider T, Moller I, Sucker A, Paschen A, Schadendorf D, et al: Is there a role for immune checkpoint blockade in metastatic uveal melanoma? J Transl Med 2015;13:2057.
2.
Lane AM, Kim IK, Gragoudas ES: Long-term risk of melanoma-related mortality for patients with uveal melanoma treated with proton beam therapy. JAMA Ophthalmol 2015;133:792-796.
3.
Jovanovic P, Mihajlovic M, Djordjevic-Jocic J, Vlajkovic S, Cekic S, Stefanovic V: Ocular melanoma: an overview of the current status. Int J Clin Exp Pathol 2013;6:1230-1244.
4.
Ventura BV, Quezada C, Maloney SC, Fernandes BF, Antecka E, Martins C, et al: Expression of the metastasis suppressor BRMS1 in uveal melanoma. Ecancermedicalscience 2014;8:410.
5.
Shields CL, Kaliki S, Hutchinson A, Nickerson S, Patel J, Kancherla S, et al: Iris nevus growth into melanoma: analysis of 1611 consecutive eyes: the ABCDEF guide. Ophthalmology 2013;120:766-772.
6.
Shields CL, Furuta M, Berman EL, Zahler JD, Hoberman DM, Dinh DH, et al: Choroidal nevus transformation into melanoma: analysis of 2,514 consecutive cases. Arch Ophthalmol 2009;127:981-987.
7.
Shields CL, Cater J, Shields JA, Singh AD, Santos MC, Carvalho C: Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol 2000;118:360-364.
8.
Shields CL, Furuta M, Thangappan A, Nagori S, Mashayekhi A, Lally DR, et al: Metastasis of uveal melanoma millimeter-by-millimeter in 8,033 consecutive eyes. Arch Ophthalmol 2009;127:989-998.
9.
Kaliki S, Shields CL, Shields JA: Uveal melanoma: estimating prognosis. Indian J Ophthalmol 2015;63:93-102.
10.
Collaborative Ocular Melanoma Study Group: Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS report No. 15. Arch Ophthalmol 2001;119:670-676.
11.
Bravo-Filho V, Bakalian S, Blanco P, Lim L, Antecka E, Mansure J, et al: FOXO1 expression in uveal melanoma and ocular tissues of normal eyes. Invest Ophthalmol Vis Sci 2014;55:5058.
12.
Frye RA: Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun 1999;260:273-279.
13.
Frye RA: Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 2000;273:793-798.
14.
North BJ, Marshall BL, Borra MT, Denu JM, Verdin E: The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 2003;11:437-444.
15.
Kozako T, Suzuki T, Yoshimitsu M, Arima N, Honda S, Soeda S: Anticancer agents targeted to sirtuins. Molecules 2014;19:20295-20313.
16.
Vaquero A, Scher MB, Lee DH, Sutton A, Cheng HL, Alt FW, et al: SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev 2006;20:1256-1261.
17.
Jin YH, Kim YJ, Kim DW, Baek KH, Kang BY, Yeo CY, et al: Sirt2 interacts with 14-3-3 beta/gamma and down-regulates the activity of p53. Biochem Biophys Res Commun 2008;368:690-695.
18.
Botta G, De Santis LP, Saladino R: Current advances in the synthesis and antitumoral activity of SIRT1-2 inhibitors by modulation of p53 and pro-apoptotic proteins. Curr Med Chem 2012;19:5871-5884.
19.
Taylor DM, Maxwell MM, Luthi-Carter R, Kazantsev AG: Biological and potential therapeutic roles of sirtuin deacetylases. Cell Mol Life Sci 2008;65:4000-4018.
20.
Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al: Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 2008;13:454-463.
21.
Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, et al: Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem Biophys Res Commun 2003;309:558-566.
22.
Kim HS, Vassilopoulos A, Wang RH, Lahusen T, Xiao Z, Xu X, et al: SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 2011;20:487-499.
23.
Ming M, Qiang L, Zhao B, He YY: Mammalian SIRT2 inhibits keratin 19 expression and is a tumor suppressor in skin. Exp Dermatol 2014;23:207-209.
24.
Bajpe PK, Prahallad A, Horlings H, Nagtegaal I, Beijersbergen R, Bernards R: A chromatin modifier genetic screen identifies SIRT2 as a modulator of response to targeted therapies through the regulation of MEK kinase activity. Oncogene 2015;34:531-536.
25.
Remmele W, Stegner HE: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue (in German). Pathologe 1987;8:138-140.
26.
Rush DS, Tan J, Baergen RN, Soslow RA: h-Caldesmon, a novel smooth muscle-specific antibody, distinguishes between cellular leiomyoma and endometrial stromal sarcoma. Am J Surg Pathol 2001;25:253-258.
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