HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells
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Weiwen He1,2,*, Yanna Wu1,2,*, Xiaomei Tang1,2, Yong Xia2, Guozhen He1,2, Zhiqun Min3, Chun Li1,2, Shiqiu Xiong4, Zhi Shi5, Yongjian Lu1,2, Zhongmin Yuan1,2
1Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
2Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou, China
3Clinical Laboratory Center of Molecular Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
4Department of Biochemistry, University of Leicester, Leicester, UK
5Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
*These authors contributed equally to this work
Zhongmin Yuan, e-mail: [email protected]
Keywords: neuroblastoma, Fra-1/c-Jun dimer, MKK7, HDAC inhibitor, proliferation
Received: August 02, 2015 Accepted: December 23, 2015 Published: December 30, 2015
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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