Tumour Expression of Histone Deacetylases in Uveal Melanoma

Levinzon, Louis; Madigan, Michele C.; Nguyen, Vuong; Hasic, Enisa; Conway, Max; Cherepanoff, Svetlana

doi:10.1159/000490038

Cited by 13 publications

(22 citation statements)

References 42 publications

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“…The use of histone deacetylases inhibitors proved to reverse H2A hyperubiquitination, inducing cell differentiation and inhibiting tumor growth ( 175 ). Indeed, the nuclear expression of several histone deacetylases has been found in UMs, confirming the role of this epigenetic alteration as a potential therapeutic target ( 177 ).…”

Section: Genetic and Epigenetic Features In Uveal Melanomamentioning

confidence: 73%

Current molecular and clinical insights into uveal melanoma (Review)

et al. 2021

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Uveal melanoma (UM) represents the most prominent primary eye cancer in adults. With an incidence of approximately 5 cases per million individuals annually in the United States, UM could be considered a relatively rare cancer. The 90-95% of UM cases arise from the choroid. Diagnosis is based mainly on a clinical examination and ancillary tests, with ocular ultrasonography being of greatest value. Differential diagnosis can prove challenging in the case of indeterminate choroidal lesions and, sometimes, monitoring for documented growth may be the proper approach. Fine needle aspiration biopsy tends to be performed with a prognostic purpose, often in combination with radiotherapy. Gene expression profiling has allowed for the grading of UMs into two classes, which feature different metastatic risks. Patients with UM require a specialized multidisciplinary management. Primary tumor treatment can be either enucleation or globe preserving. Usually, enucleation is reserved for larger tumors, while radiotherapy is preferred for small/medium melanomas. The prognosis is unfavorable due to the high mortality rate and high tendency to metastasize. Following the development of metastatic disease, the mortality rate increases to 80% within one year, due to both the absence of an effective treatment and the aggressiveness of the condition. Novel molecular studies have allowed for a better understanding of the genetic and epigenetic mechanisms involved in UM biological activity, which differs compared to skin melanomas. The most commonly mutated genes are GNAQ, GNA11 and BAP1. Research in this field could help to identify effective diagnostic and prognostic biomarkers, as well as novel therapeutic targets.

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Section: Genetic and Epigenetic Features In Uveal Melanomamentioning

confidence: 73%

Current molecular and clinical insights into uveal melanoma (Review)

et al. 2021

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“…HDAC IHC expression has been described in several tumor types, being associated with important clinicopathological parameters, including patients’ prognosis [ 18 , 19 , 20 , 22 , 24 , 25 , 26 ]. 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 ].…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Levidou

Gajdzis

Cassoux

et al. 2021

Cancers

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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.

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“…Then, with the aim to deeply investigate the biological properties of the four most promising hydroxamic derivatives, we performed in vitro assays on isolated Class I enzymes (HDACs 1,3,8) and Class II HDAC6. Considering the expression of histone deacetylases in UM 23 and the potential therapeutic role of HDACIs in this tumour 5 , the same compounds were selected for further tests on UM cell lines. Finally, docking studies were performed to investigate their binding mode.…”

Section: Introductionmentioning

confidence: 99%

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Nencetti

Cuffaro

Nuti

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA.

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Tumour Expression of Histone Deacetylases in Uveal Melanoma

Cited by 13 publications

References 42 publications

Current molecular and clinical insights into uveal melanoma (Review)

Current molecular and clinical insights into uveal melanoma (Review)

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

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

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