Histone Deacetylase Inhibitors Induce Growth Arrest and Differentiation in Uveal Melanoma

Abstract

Purpose Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma and metastasis (UM). The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM. Experimental Design In silico screens were performed to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid, trichostatin A, LBH-589 and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, BrdU incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model. Results HDAC inhibitors induced morphologic differentiation, cell cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. Valproic acid inhibited the growth of UM tumors in vivo. Conclusions These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM.

Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma

“…Histone deacetylase inhibitors have shown to reverse the effects of BAP1 depletion in uveal melanoma cells. 32 As therapeutic options emerge, it is important to be able to rapidly identify the patients, enucleated and conservatively treated patients, who would benefit from a specific intervention. Given the costs of BAP1 mutation analysis, immunohistochemistry offers an economical and fast alternative.…”

The epigenetic landscape of renal cancer

“…However, no large-scale trial for demethylation treatment in RCC is currently underway. Trials of HDAC inhibitors in patients with advanced RCC are currently underway [249][250][251] . HDAC inhibitors might be particularly effective in patients with BAP1 mutations as, in addition to reversing gene silencing initiated by aberrant promoter methylation, HDAC inhibitors might also have the ability to reverse H2A ubiquitylation, which is associated with loss of BAP1 (REF.…”

Molecular pathology of uveal melanoma

“…8,[152][153][154] It is, however, worth mentioning the potential targets for UM therapy, which have been revealed by efforts Update in the molecular pathology of uveal melanoma SE Coupland et al unravelling key signalling cascades implicated in the development and progression of UM. These include the inhibitors of the: MAPK/MEK signalling pathway; PI3K/AKT pathway at the level of AKT; mTOR; mTOR blockade combined with an IGF-1R antibody; tyrosine kinases; c-Met pathway; CXCR4 and histone deacetylase.…”

“…These include the inhibitors of the: MAPK/MEK signalling pathway; PI3K/AKT pathway at the level of AKT; mTOR; mTOR blockade combined with an IGF-1R antibody; tyrosine kinases; c-Met pathway; CXCR4 and histone deacetylase. 154 The progress of these varied approaches will be followed with enthusiasm by clinicians, researchers, and patients alike.…”