Class II-specific histone deacetylase inhibitors MC1568 and MC1575 suppress IL-8 expression in human melanoma cells

Pigment Cell Melanoma Res. 2013 Mar;26(2):193-204. doi: 10.1111/pcmr.12049. Epub 2013 Jan 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA-Directed RNA Polymerases / metabolism
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Interleukin-8 / genetics*
  • Interleukin-8 / metabolism
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Melanoma / pathology
  • Promoter Regions, Genetic
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • Pyrroles / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor TFIIB / metabolism
  • Transcription, Genetic / drug effects
  • Uveal Neoplasms / enzymology
  • Uveal Neoplasms / genetics
  • Uveal Neoplasms / pathology

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Interleukin-8
  • MC1568
  • MC1575
  • Proto-Oncogene Proteins c-jun
  • Pyrroles
  • RNA, Messenger
  • Transcription Factor AP-1
  • Transcription Factor TFIIB
  • DNA-Directed RNA Polymerases
  • Histone Deacetylases
  • Tetradecanoylphorbol Acetate

Supplementary concepts

  • Uveal melanoma