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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma
Solange Landreville1, Olga A Agapova, Katie A Matatall
1Departments of Ophthalmology & Visual Sciences, Otolaryngology, and Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
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.
Insights
Histone deacetylase (HDAC) inhibitors promote differentiation and cell cycle exit in uveal melanoma (UM) cells. These compounds show potential for treating metastatic UM by inducing dormancy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Metastasis causes most cancer deaths, with limited therapies targeting its molecular drivers.
- Loss of the BAP1 tumor suppressor gene in uveal melanoma (UM) correlates with dedifferentiation and metastasis.
- There is a critical need for agents that reverse the metastatic phenotype in UM.
Purpose of the Study:
- To identify therapeutic agents capable of reversing the phenotypic consequences of BAP1 loss in UM.
- To explore compounds that can restore melanocytic differentiation in UM cells.
Main Methods:
- In silico screening using Gene Set Enrichment Analysis and Connectivity Map to identify differentiating compounds.
- In vitro evaluation of compounds (e.g., Valproic Acid) using assays for morphology, viability, cell cycle, gene expression, and histone modifications.
- In vivo assessment using a murine xenograft model for tumorigenicity.
Main Results:
- Histone deacetylase (HDAC) inhibitors induced differentiation, cell-cycle arrest, and a melanocytic gene expression profile in UM cells.
- Valproic acid (VPA) demonstrated efficacy in inhibiting UM tumor growth in vivo.
- HDAC inhibition was linked to increased histone acetylation and ubiquitination.
Conclusions:
- HDAC inhibitors show therapeutic promise for UM by inducing cellular differentiation.
- These agents may be valuable for achieving prolonged dormancy of micrometastatic UM disease.
- Targeting HDACs represents a potential strategy to combat UM metastasis.
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