Abstract
Here, we explored the effects of the novel class II-specific histone deacetylase inhibitors (HDACis) MC1568 and MC1575 on interleukin-8 (IL-8) expression and cell proliferation in cutaneous melanoma cell line GR-M and uveal melanoma cell line OCM-3 upon stimulation with phorbol 12-myristate 13-acetate (PMA). We found that PMA upregulated IL-8 transcription via the AP-1 binding site and identified c-Jun as the transcription factor involved in this eventS. MC1568 and MC1575 inhibited IL-8 levels and cell proliferation in either unstimulated or PMA-stimulated melanoma cells. They acted by suppressing (i) c-Jun binding to the IL-8 promoter, (ii) recruitment of histones 3 and 4, RNA polymerase II and TFIIB to the c-Jun promoter, and (iii) c-Jun expression. Our findings provide new insights into mechanisms underlying anti-tumoral activities of class II-specific HDACis in human melanoma and suggest that they may constitute a novel therapeutic strategy for improving the treatment of this cancer.
© 2012 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA-Directed RNA Polymerases / metabolism
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Knockdown Techniques
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Histones / metabolism
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Humans
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Hydroxamic Acids / pharmacology*
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Interleukin-8 / genetics*
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Interleukin-8 / metabolism
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Melanoma / enzymology
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Melanoma / genetics*
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Melanoma / pathology
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Promoter Regions, Genetic
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Protein Binding / drug effects
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Protein Binding / genetics
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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Pyrroles / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Skin Neoplasms / enzymology
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factor AP-1 / metabolism
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Transcription Factor TFIIB / metabolism
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Transcription, Genetic / drug effects
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Uveal Neoplasms / enzymology
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Uveal Neoplasms / genetics
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Uveal Neoplasms / pathology
Substances
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Histone Deacetylase Inhibitors
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Histones
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Hydroxamic Acids
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Interleukin-8
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MC1568
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MC1575
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Proto-Oncogene Proteins c-jun
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Pyrroles
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RNA, Messenger
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Transcription Factor AP-1
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Transcription Factor TFIIB
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DNA-Directed RNA Polymerases
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Histone Deacetylases
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Tetradecanoylphorbol Acetate