Histone Deacetylase (HDAC)-1, -2, -4, and -6 in Uveal Melanomas: Associations with Clinicopathological Parameters and Patients’ Survival

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.

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer

“…Mechanistically, tubulin acetylation stabilizes the level of the anti-apoptotic protein Mcl-1 by protecting it from degradation [69]. In line with these studies, aberrant expression of tubulin deacetylase HDAC6 has been reported in several cancer cell lines and tumor models [70,71]. In addition, upregulation of HDAC6 increases cell motility in breast cancer cells, thus contributing to cancer metastasis [72], whereas in glioblastoma cells genetic silencing of HDAC6 decreases cellular malignancy and reverses the mesenchymal phenotype [73,74].…”

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

“…In line with previous studies, which confirmed HDAC gene [ 243 , 244 ] and protein [ 245 ] expression in UM, the authors evaluated HDAC-1, HDAC-2, HDAC-4 and HDAC-6 through IHC and aimed to determine their role as prognostic factors [ 193 ]. HDAC-1 and HDAC-2 had both nuclear and cytoplasmic expression, whereas HDAC-4 and HDAC-6 were mostly expressed in the cytoplasm of UM cells [ 193 ]. Among the four studied HDACs isoforms, HDAC-2 was the most frequently expressed, with a more significant nuclear expression pattern, and the expression of HDAC-2 the only proven to be an independent factor of better survival in UM [ 193 ].…”

“…Consequently, HDAC inhibitors have constituted promising anti-neurodegeneration and anti-cancer therapies [ 241 , 242 ]. The prognostic significance of HDAC expression in UM was recently evaluated in a study involving 75 UM cases [ 193 ]. In line with previous studies, which confirmed HDAC gene [ 243 , 244 ] and protein [ 245 ] expression in UM, the authors evaluated HDAC-1, HDAC-2, HDAC-4 and HDAC-6 through IHC and aimed to determine their role as prognostic factors [ 193 ].…”

“…The prognostic significance of HDAC expression in UM was recently evaluated in a study involving 75 UM cases [ 193 ]. In line with previous studies, which confirmed HDAC gene [ 243 , 244 ] and protein [ 245 ] expression in UM, the authors evaluated HDAC-1, HDAC-2, HDAC-4 and HDAC-6 through IHC and aimed to determine their role as prognostic factors [ 193 ]. HDAC-1 and HDAC-2 had both nuclear and cytoplasmic expression, whereas HDAC-4 and HDAC-6 were mostly expressed in the cytoplasm of UM cells [ 193 ].…”

“…HDAC-1 and HDAC-2 had both nuclear and cytoplasmic expression, whereas HDAC-4 and HDAC-6 were mostly expressed in the cytoplasm of UM cells [ 193 ]. Among the four studied HDACs isoforms, HDAC-2 was the most frequently expressed, with a more significant nuclear expression pattern, and the expression of HDAC-2 the only proven to be an independent factor of better survival in UM [ 193 ]. This study provides additional evidence on the potential role of HDACs in UM development and progression, suggesting that inhibition of HDAC could constitute a relevant therapeutic strategy [ 241 ].…”