title: HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.
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.
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Weiwen
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Tang
authors.affiliation: Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: He
authors.affiliation: Clinical Laboratory Center of Molecular Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Min
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, UK.
authors.forename: Shiqiu
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D000099169:Fos-Related Antigen 1
chemical_list: D056572:Histone Deacetylase Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D016760:Proto-Oncogene Proteins c-fos; D019908:Proto-Oncogene Proteins c-raf; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C482569:MAP2K7 protein, human
keywords: Fra-1/c-Jun dimer; HDAC inhibitor; MKK7; neuroblastoma; proliferation