Abstract
Simple SummaryHistone Deacetylases (HDACs) have been reportedly associated with tumor development and progression in several types of human malignancy, being currently investigated as potential targets of anti-cancer therapy. The aim of this study is to assess the clinical significance and prognostic role of the of HDAC-1, -2, -4, and -6 immunohistochemical expression, in 75 uveal melanoma (UM) cases. HDACs are differentially expressed in UMs, HDAC-2 being the most frequently expressed isoform, whereas cytoplasmic expression of class I HDAC isoforms is also observed. Additionally, HDAC-1 was associated with increased tumor size, HDAC-6 with mitotic index, and HDAC-2 with epithelioid cell morphology and presence of tumor-infiltrating lymphocytes, both parameters of adverse prognosis. Moreover, our data support a significant association of HDAC-2 with patients’ improved OS. These findings suggest that HDACs, and especially HDAC-2, may be implicated in the formation and progression of UM.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.
Highlights
Epigenetic and post-translational modifications have been suggested to comprise an important regulatory mechanism of gene transcription, being increasingly correlated with carcinogenesis as well as with neoplastic disease progression
Cell type was categorized according to the modified Callender classification system as follows: 18 (24%) cases comprised of epithelioid cell melanomas, 21 (28%) of spindle cell melanomas, and the remaining 36 (48%) melanomas were of mixed-cell type
The present study shows that Histone deacetylases (HDACs) are differentially expressed in Uveal melanoma (UM), HDAC-2 being the most frequently expressed isoform, whereas cytoplasmic expression of class I
Summary
Epigenetic and post-translational modifications have been suggested to comprise an important regulatory mechanism of gene transcription, being increasingly correlated with carcinogenesis as well as with neoplastic disease progression. The acetylation of core histones is tightly regulated by the balance of two counteracting enzymatic activities: those of histone acetyl transferases (HATs) and of histone deacetylaces (HDACs) [2,3]. The latter remove acetyl groups from histone specific lysine residues, thereby increasing the charge density on the N-termini of the core histones, strengthening histone tail-DNA interactions, and blocking access of the transcriptional machinery to the DNA template, leading to transcriptional repression [3].
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