Histone Deacetylase (HDAC)-1, -2, -4, and -6 in Uveal Melanomas: Associations with Clinicopathological Parameters and Patients’ Survival
Georgia Levidou, Paweł Gajdzis, Nathalie Cassoux, Piotr Donizy, Christos Masaoutis, Małgorzata Gajdzis, Sophie Gardrat, Alexandros Pergaris, Eugene Danas, Jerzy Klijanienko, Stamatios Theocharis
Abstract
Background: Uveal melanoma (UM) represents the most common primary intraocular malignancy in adults, exerting high metastatic potential and poor prognosis. Histone deacetylases (HDACs) play a key role in carcinogenesis, and HDAC inhibitors (HDACIs) are currently being explored as anti-cancer agents in clinical settings. The aim of this study was to evaluate the clinical significance of HDAC-1, -2, -4, and -6 expression in UM. Methods: HDAC-1, -2, -4, and -6 expression was examined immunohistochemically in 75 UM tissue specimens and was correlated with tumors’ clinicopathological characteristics, the presence of tumor-infiltrating lymphocytes (TILS), as well as with our patients’ overall survival (OS). Results: HDAC-2 was the most frequently expressed isoform (66%), whereas we confirmed in addition to the expected nuclear expression the presence of cytoplasmic expression of class I HDAC isoforms, namely HDAC-1 (33%) and HDAC-2 (9.5%). HDAC-4 and -6 expression was cytoplasmic. HDAC-1 nuclear expression was associated with increased tumor size (p = 0.03), HDAC-6 with higher mitotic index (p = 0.03), and nuclear HDAC-2 with epithelioid cell morphology (p = 0.03) and presence of tumor-infiltrating lymphocytes (p = 0.04). The association with the remaining parameters including Monosomy 3 was not significant. Moreover, the presence as well as the nuclear expression pattern of HDAC-2 were correlated with patients’ improved OS and remained significant in multivariate survival analysis. Conclusions: These findings provide evidence for a potential role of HDACs and especially HDAC-2 in the biological mechanisms governing UM evolution and progression.