HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.
HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.
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HDAC 抑制剂通过转录下调神经母细胞瘤细胞中的 MKK7 和 Raf1 来抑制 c-Jun/Fra-1 介导的增殖
DOI：
10.18632/oncotarget.6797
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
Yuan Z
中科院分区：
文献类型：
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作者：
He W;Wu Y;Tang X;Xia Y;He G;Min Z;Li C;Xiong S;Shi Z;Lu Y;Yuan Z
激活蛋白1 （Activator protein 1, AP-1）是一种由bZIP蛋白二聚体成员组成的转录因子，在人类癌细胞中经常被解除调控。在这项研究中，我们旨在鉴定一种对神经母细胞瘤细胞增殖至关重要的致癌AP-1二聚体，并研究新一代抗癌药物组蛋白去乙酰化酶抑制剂（HDACIs）是否可以靶向AP-1二聚体。我们在这里报道，包括trichostatin A、亚甲基苯胺羟肟酸、丙戊酸和M344在内的hdac可以在抑制细胞生长之前通过转录抑制c-Jun和fr -1。c-Jun优先与fr -1作为异源二聚体相互作用，负责AP-1活性，对细胞生长至关重要。从机制上讲，hdac通过转录下调Raf1并随后降低MEK1/2-ERK1/2活性来抑制fr -1的表达。出乎意料的是，HDACI处理导致MKK7蛋白和mRNA水平下调。对MKK7基因5 '侧序列的缺失分析显示，与HDACI下调有关的一个主要元件位于转录起始位点的- 149至- 3。敲低MKK7而不敲低MKK4显著降低JNK/c-Jun活性和增殖，而异位MKK7- jnk1逆转了hdaci诱导的c-Jun抑制。此外，抑制MKK-7/c-Jun和Raf-1/ fr -1活性参与了SAHA诱导SH-SY5Y异种移植小鼠的肿瘤生长抑制作用。总之，这些发现表明，c-Jun/Fra-1二聚体对神经母细胞瘤细胞生长至关重要，hdac通过转录下调MKK7和Raf1，有效抑制了这两种癌基因。
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.