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

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.

Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

“…MC1568, a newly developed inhibitor with specificity towards Class II HDACs [76], has been extensively investigated in cancerous and non-cancerous cell types and showed effective inhibition of Class II HDACs [77,78]. Incubation of freshly isolated mouse HSCs with MC1568 clearly inhibits the proliferation and markedly decreases the differentiation of the HSCs toward myofibroblast-like cells.…”

Tumour Expression of Histone Deacetylases in Uveal Melanoma

“…HDAC inhibitors are promising anticancer agents with effects reported in multiple human malignancies and cell lines [19]. These agents display strong selectivity against malignant cells [20], but relatively low toxicity to normal cells [19].…”

“…These agents display strong selectivity against malignant cells [20], but relatively low toxicity to normal cells [19]. HDAC inhibitors display a broad spectrum of actions targeting the hallmark aberrant behaviours of cancer cells [9,17].…”

Selective class IIa HDAC inhibitors: myth or reality

“…3, please note that in Fig. 3 we provide for MC1568 the recently reassigned structure [72]) are two class II HDACs inhibitors specific for HDAC4 and HDAC6 [73][74][75][76]. They are derivatives of classical class I HDACs inhibitors aroyl-pyrrolyl-hydroxyamides (APHAs), showing selectivity towards class IIa HDACs.…”

“…Compared to the original class I inhibitors, they exhibit a decreased cytotoxic effect [73]. Despite this fact, MC1568 and MC1575 show some cytostatic effects in melanoma cells [76] and in ER ? breast cancer cells [74].…”