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Cancer Therapy: Preclinical

Histone Deacetylase Inhibitors Induce Growth Arrest and Differentiation in Uveal Melanoma

Solange Landreville, Olga A. Agapova, Katie A. Matatall, Zachary T. Kneass, Michael D. Onken, Ryan S. Lee, Anne M. Bowcock and J. William Harbour
Solange Landreville
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Olga A. Agapova
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Katie A. Matatall
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Zachary T. Kneass
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Michael D. Onken
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Ryan S. Lee
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Anne M. Bowcock
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J. William Harbour
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DOI: 10.1158/1078-0432.CCR-11-0946 Published January 2012
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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 (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. Clin Cancer Res; 18(2); 408–16. ©2011 AACR.

This article is featured in Highlights of This Issue, p. 321

See commentary by Woodman, p. 323

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received April 12, 2011.
  • Revision received October 15, 2011.
  • Accepted October 20, 2011.
  • ©2011 American Association for Cancer Research.

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Clinical Cancer Research: 18 (2)
January 2012
Volume 18, Issue 2
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Histone Deacetylase Inhibitors Induce Growth Arrest and Differentiation in Uveal Melanoma
Solange Landreville, Olga A. Agapova, Katie A. Matatall, Zachary T. Kneass, Michael D. Onken, Ryan S. Lee, Anne M. Bowcock and J. William Harbour
Clin Cancer Res January 15 2012 (18) (2) 408-416; DOI: 10.1158/1078-0432.CCR-11-0946

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Histone Deacetylase Inhibitors Induce Growth Arrest and Differentiation in Uveal Melanoma
Solange Landreville, Olga A. Agapova, Katie A. Matatall, Zachary T. Kneass, Michael D. Onken, Ryan S. Lee, Anne M. Bowcock and J. William Harbour
Clin Cancer Res January 15 2012 (18) (2) 408-416; DOI: 10.1158/1078-0432.CCR-11-0946
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Clinical Cancer Research
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