ArticleOncotarget2016
HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- CpG hypermethylation and WNT/AP-1 cooperativity define the epigenetic landscape and a clinical subgroup of high-risk pediatric adrenocortical carcinoma.Nature communications · 2026Article
- An Integrated Machine-Learning and Reverse Network-Pharmacology Pipeline RevealsInternational journal of molecular sciences · 2026Article
- Fra-1 promotes gastric cancer progression by regulating macrophage polarization and transcriptionally activating HMGA2 expression.Cell death discovery · 2025Article
- Jun, an Oncological Foe or Friend?International journal of molecular sciences · 2025Review
- Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma.Cancers · 2022Review
- An autophagy-related four-lncRNA signature helps to predict progression-free survival of neuroblastoma patients.Frontiers in oncology · 2022Article
- The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology.Cancers · 2021Review
- Review
- Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway.Frontiers in cell and developmental biology · 2020Article
- Expression and function of FRA1 protein in tumors.Molecular biology reports · 2020Review
- HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice.OncoTargets and therapy · 2020Article
- Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7.Frontiers in cellular neuroscience · 2019Article
- Review
- Proteome and Acetylome Analysis Identifies Novel Pathways and Targets Regulated by Perifosine in Neuroblastoma.Scientific reports · 2017Article
- Targeting EP4 downstream c-Jun through ERK1/2-mediated reduction of DNMT1 reveals novel mechanism of solamargine-inhibited growth of lung cancer cells.Journal of cellular and molecular medicine · 2017Article
- Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.Cell death & disease · 2017Article
- HTP Nutraceutical Screening for Histone Deacetylase Inhibitors and Effects of HDACis on Tumor-suppressing miRNAs by Trichostatin A and Grapeseed (Vitis vinifera) in HeLa cells.Cancer genomics & proteomics · 2017Article
- A plasma mir-125a-5p as a novel biomarker for Kawasaki disease and induces apoptosis in HUVECs.PloS one · 2017Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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