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 (UM) and metastasis. 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 done to identify therapeutic 
compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis 
and Connectivity Map databases. Valproic acid (VPA), trichostatin A, LBH-589, 
and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells 
using morphologic evaluation, MTS viability assays, bromodeoxyuridine 
incorporation, flow cytometry, clonogenic assays, gene expression profiling, 
histone acetylation and ubiquitination assays, and a murine xenograft 
tumorigenicity model.
RESULTS: Histone deacetylase (HDAC) inhibitors induced morphologic 
differentiation, cell-cycle exit, and a shift to a differentiated, melanocytic 
gene expression profile in cultured UM cells. VPA 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.