Abstract
Activator protein 1 (AP-1) is a transcriptional factor composed of the dimeric members of bZIP proteins, which are frequently deregulated in human cancer cells. In this study, we aimed to identify an oncogenic AP-1 dimer critical for the proliferation of neuroblastoma cells and to investigate whether histone deacetylase inhibitors (HDACIs), a new generation of anticancer agents, could target the AP-1 dimer. We report here that HDACIs including trichostatin A, suberoylanilidehydroxamic acid, valproic acid and M344 can transcriptionally suppress both c-Jun and Fra-1, preceding their inhibition of cell growth. c-Jun preferentially interacting with Fra-1 as a heterodimer is responsible for AP-1 activity and critical for cell growth. Mechanistically, HDACIs suppress Fra-1 expression through transcriptionally downregulating Raf1 and subsequently decreasing MEK1/2-ERK1/2 activity. Unexpectedly, HDACI treatment caused MKK7 downregulation at both the protein and mRNA levels. Deletion analysis of the 5′-flanking sequence of the MKK7 gene revealed that a major element responsible for the downregulation by HDACI is located at −149 to −3 relative to the transcriptional start site. Knockdown of MKK7 but not MKK4 remarkably decreased JNK/c-Jun activity and proliferation, whereas ectopic MKK7-JNK1 reversed HDACI-induced c-Jun suppression. Furthermore, suppression of both MKK-7/c-Jun and Raf-1/Fra-1 activities was involved in the tumor growth inhibitory effects induced by SAHA in SH-SY5Y xenograft mice. Collectively, these findings demonstrated that c-Jun/Fra-1 dimer is critical for neuroblastoma cell growth and that HDACIs act as effective suppressors of the two oncogenes through transcriptionally downregulating MKK7 and Raf1.
Highlights
Neuroblastoma (NB), which is typically derived from neural crest tissues of the sympathetic nervous system, accounts for approximately 10% of all childhood cancers and 50% of childhood cancer deaths [1].Amplification of the MYCN is the predominant marker for aggressive NB and correlates with poor prognosis, found in 20% cases of NBs [2]
Treating cells with 500 nM TSA, 1 μM SAHA, 1 μM M344 or 2 mM VPA for 1 hour induced a robust increase in both H3 lysine 27 and H4 lysine 12 acetylation (Figure 1A), and remarkably induces p21 expression [12], suggesting that Histone deacetyltransferases (HDACs) activities were efficiently suppressed by the histone deacetylase inhibitors (HDACIs) used
MTT assays demonstrated that all HDACIs used remarkably inhibited the proliferation of the four cell lines starting at 12 hours post-treatment and induced greater suppression lasting up to 18 and 24 hours (P < 0.05, Figure 1B)
Summary
Neuroblastoma (NB), which is typically derived from neural crest tissues of the sympathetic nervous system, accounts for approximately 10% of all childhood cancers and 50% of childhood cancer deaths [1].Amplification of the MYCN is the predominant marker for aggressive NB and correlates with poor prognosis, found in 20% cases of NBs [2]. As NBs that are not curable www.impactjournals.com/oncotarget with current therapeutic modalities commonly exhibit defects in growth arrest and apoptosis [3], identifying the factors that play critical roles in driving NB malignant transformation or progression, as well as promoting survival and proliferation is attractive for developing therapeutic targets. Specific AP-1 dimers have been shown to be associated with carcinogenesis and cancer development. The c-Jun/c-Fos dimer was shown to promote proliferation in lung cancer via upregulating cyclin D1 [6]. Fra-1 was shown to associate with c-Jun, transactivating MMP-1 to increase malignant invasion in breast cancer [7] and osteosarcoma cells [8]. Fra-1 was found to upregulate and dimerize with JunB, contributing to the malignant phenotype [9]. Identifying and inactivating specific AP-1 dimers with oncogenic roles appear to be a promising strategy for impairing malignant phenotypes in different tumor types
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