Expression of HDACs 1, 3 and 8 Is Upregulated in the Presence of Infiltrating Lymphocytes in Uveal Melanoma

Abstract

In Uveal Melanoma (UM), an inflammatory phenotype is strongly associated with the development of metastases and with chromosome 3/BAP1 expression loss. As an increased expression of several Histone Deacetylases (HDACs) was associated with loss of chromosome 3, this suggested that HDAC expression might also be related to inflammation. We analyzed HDAC expression and the presence of leukocytes by mRNA expression in two sets of UM (Leiden and TCGA) and determined the T lymphocyte fraction through ddPCR. Four UM cell lines were treated with IFNγ (50IU, 200IU). Quantitative PCR (qPCR) was used for mRNA measurement of HDACs in cultured cells. In both cohorts (Leiden and TCGA), a positive correlation occurred between expression of HDACs 1, 3 and 8 and the presence of a T-cell infiltrate, while expression of HDACs 2 and 11 was negatively correlated with the presence of tumor-infiltrating macrophages. Stimulation of UM cell lines with IFNγ induced an increase in HDACs 1, 4, 5, 7 and 8 in two out of four UM cell lines. We conclude that the observed positive correlations between HDAC expression and chromosome 3/BAP1 loss may be related to the presence of infiltrating T cells.

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

“…According to the modified Callender classification, it has been traditionally considered to have a strong correlation with mortality; spindle cell UMs seem to have the best prognosis, mixed cell type UMs an intermediate prognosis, and epitheloid cell type UMs the worst prognosis [ 30 , 32 , 33 ], a finding that was also recapitulated in our cohort in our survival analysis. In contrast to the previously reported results by Souri et al [ 16 ], in our cohort, only HDAC-2 immunoexpression was correlated with the presence of ILS, being higher in cases with a small number of TILS, which is also considered to be another factor of poor prognosis [ 30 ].…”

“…Importantly, HDAC-2 expression was associated with tumor histological type, being higher in the epithelioid cell than in spindle cell morphology. A similar association regarding the expression of HDAC-1 by gene expression profiling has been reported by Souri et al [ 16 ]. Tumor cell type has been considered an important prognostic factor for patients with UMs.…”

“…Information on HDAC IHC expression in UMs remains scarce, as the available data so far are limited to one recent study conducted on 16 UM specimens without, however, any attempt to correlate it with patients’ clinical information [ 17 ]. Moreover, Souri et al, in two recent studies, report the expression of HDAC-1, -3, -4, -8 using gene expression profiling [ 15 , 16 ]. The present study assessed the clinical significance of HDAC-1, -2, -4, and -6 immunohistochemical expression in UMs.…”

“…Apart from the increasing research of HDACIs in UMs, there is, to the best of our knowledge, to date, no comprehensive available information regarding the clinical significance of HDACs expression. Souri et al recently described the expression of HDACs using gene expression profiling [ 15 , 16 ], while only one recent observational immunohistochemical study exists investigating the expression of HDACs in 16 UM cases [ 17 ]. In view of the above considerations, the present study aims to assess the immunohistochemical expression of several members of HDAC protein family classes I and II (a,b), namely HDAC-1, -2, -4, and -6, in UM specimens, in association with clinicopathological parameters as well as patients’ overall survival (OS) and disease-free survival (DFS).…”

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

“…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 ].…”