The Role of Histone Deacetylase Inhibitors in Uveal Melanoma: Current Evidence

Abstract

Uveal melanoma is the most common intraocular malignancy in adults, representing approximately 3% of all melanoma cases. Despite progress in chemotherapy, radiation and surgical treatment options, the prognosis and survival rates remain poor. Acetylation of histone proteins causes transcription of genes involved in cell growth, DNA replication and progression of cell cycle. Overexpression of histone deacetylases occurs in a wide spectrum of malignancies. Histone deacetylase inhibitors block the action of histone deacetylases, leading to inhibition of tumor cell proliferation. This article reviewed the potential therapeutic effects of histone deacetylase inhibitors on uveal melanoma. MEDLINE database was used under the key words/phrases: histone deacetylase, inhibitors, uveal melanoma and targeted therapies for uveal melanoma. A total of 47, English articles, not only referring to uveal melanoma, published up to February 2018 were used. Valproic acid, trichostatin A, tenovin-6, depsipeptide, panobinostat (LBH-589), vorinostat (suberanilohydroxamic acid) entinostat (MS-275), quisinostat, NaB, JSL-1, MC1568 and MC1575 are histone deacetylase inhibitors that have demonstrated promising antitumor effects against uveal melanoma. Histone deacetylase inhibitors represent a promising therapeutic approach for the treatment of uveal melanoma.

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma

“…Inhibition of multiple HDACs, using the pan-HDAC inhibitor panobinostat was found to be superior to multiple other epigenetic inhibitors including EZH2, DOTL1, HATs, and LSD1 in enhancing the cytotoxic activity of MEK inhibition. There is already good evidence that HDAC inhibitors, including the class III inhibitor tenovin, and a number of pan-HDAC inhibitors (TSA, depsipeptide butyrate) have activity against uveal melanoma cell lines, through affects upon FAS, p21,p27, p53, c-JUN, and b-catenin expression (55)(56)(57). In cutaneous melanoma, there is also evidence that HDAC inhibition can restore sensitivity to BRAF inhibition following the onset of resistance (58)(59)(60).…”

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

“…In the past years, a group of enzymes involved in the epigenetic regulation of gene expression, histone deacetylases (HDACs), have generated increasing interest as potential therapeutic targets for UM [4][5][6] . HDACs remove the acetyl groups from histone lysine residues from diverse protein targets, resulting in a condensed chromatin structure that downregulates gene expression, also of tumour suppressor genes 7 .…”

“…Chidamide (HBI-8000) has been approved by the Chinese FDA for relapsed or refractory PTCL in 2015 19 (Figure 1). In vitro studies with some of these HDACIs have shown a shift of the gene expression profile from Class II (high metastatic risk) to a Class I (low metastatic risk) in UM cell cultures 5 . Moreover, it has been recognised that HDAC inhibitors such as Vorinostat (SAHA) and Panobinostat (LBH589), may be useful in adjuvant therapy in patients with high-risk Class II UM playing a role in preventing the progression of micrometastatic disease 13 .…”

“…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.…”

I BET on anti‐FGFR to fight cancer resistance

“…resistance development in UMM. Vorinostat (a well‐known HDACi) is entering a Phase I and II clinical trials for UMM (NCT00121225 and NCT01587352) (Moschos et al , ) (Haas et al , ), and in the near future, the potential of epigenome‐targeting schemes will likely be better defined.…”