Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma.
OBJECTIVE
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.


METHODS
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.
Departments of Ophthalmology & Visual Sciences, Otolaryngology, and Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Solange
S
Landreville
Olga A
OA
Agapova
Katie A
KA
Matatall
Zachary T
ZT
Kneass
Michael D
MD
Onken
Ryan S
RS
Lee
Anne M
AM
Bowcock
J William
JW
Harbour
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D059186:Chemoradiotherapy, Adjuvant; D003198:Computer Simulation; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D061206:Neoplasm Micrometastasis / Q000517:prevention & control; D000077767:Panobinostat; D047368:Tumor Burden / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
D000970:Antineoplastic Agents; C400134:BAP1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; D000077337:Vorinostat; D014635:Valproic Acid; D000077767:Panobinostat; D043222:Ubiquitin Thiolesterase