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Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis.

ABSTRACT: The transcription factor AP1 (activating protein 1), a heterodimer of the JUN and FOS proteins, promotes the invasive growth and metastasis of various tumors such as squamous cell carcinoma (SCC), breast cancer, and melanoma. AP1 activity is transcriptionally induced through a positive feedback loop. We identified the histone demethylase KDM4A (lysine-specific demethylase 4A) as a key epigenetic priming factor in this positive feedback loop. KDM4A contributed to the induction of genes encoding the AP1 transcription factors and the invasive growth and metastasis of SCC. KDM4A knockdown decreased the growth factor-induced messenger RNA expression and protein abundance of AP1 family members, including JUN and FOSL1. Mechanistically, histone demethylation by KDM4A facilitated the binding of the AP1 complex to the promoters of JUN and FOSL1, thereby promoting the positive feedback loop that maintains activation of AP1. In a mouse model of SCC, KDM4A knockdown inhibited lymph node metastasis. Moreover, the abundance of KDM4A correlated with the abundance of JUN and FOSL1 in human SCC tissues, and KDM4A expression was increased in human lymph node metastases. Our studies provide insights into the epigenetic control of AP1 and tumor invasion and suggest that KDM4A could be an important therapeutic target for inhibiting invasive SCC growth and metastasis.

SUBMITTER: Ding X

PROVIDER: S-EPMC3951265 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis.

Ding Xiangming X Pan Hongya H Li Jiong J Zhong Qi Q Chen Xiaohong X Dry Sarah M SM Wang Cun-Yu CY

Science signaling 20130430 273

The transcription factor AP1 (activating protein 1), a heterodimer of the JUN and FOS proteins, promotes the invasive growth and metastasis of various tumors such as squamous cell carcinoma (SCC), breast cancer, and melanoma. AP1 activity is transcriptionally induced through a positive feedback loop. We identified the histone demethylase KDM4A (lysine-specific demethylase 4A) as a key epigenetic priming factor in this positive feedback loop. KDM4A contributed to the induction of genes encoding t ...[more]

PMID: 23633675

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Project description:While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis in HNSCC is limited. We initially performed the upstream and key nodes analysis together with whole gene microarray analysis characterized by distant metastatic potential in vivo with HNSCC cell lines and identified JunB, a member of the activator protein-1 (AP-1) family, as a key molecule in the regulation of the pathways related to distant metastasis in HNSCC. We have therefore tested the hypothesis that JunB plays a crucial role in distant metastasis in HNSCC.To study the role of JunB on metastatic potential of HNSCC, small interfering RNA (siRNA)-mediated knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (cas9) system (CRISPR/Cas9)-mediated knockout of JunB in HNSCC cells were established and the abilities of cell invasion and migration in vitro were examined. The efficacy of knockout of JunB was also examined using an experimental lung metastatic mouse model of HNSCC. In addition, to study if the role of JunB in HNSCC cell migration and invasiveness is related to epithelial-to-mesenchymal transition (EMT), cell morphology and expression of mesenchymal or epithelial marker on siRNA mediated JunB knockdown in HNSCC cells were examined with or without TGF-? stimulation.siRNA knockdown and sgRNA knockout of JunB in metastatic HNSCC cells significantly suppressed both cell invasion and migration in vitro. In addition, the knockout of JunB in metastatic HNSCC cells significantly repressed the incidence of lung metastases and prolonged the survival in vivo. However, we did not observe any change in cell morphology with the down-regulation of mesenchymal markers and up-regulation of epithelial markers in response to siRNA-mediated JunB knockdown in HNSCC cells.These results suggested that JunB could play an important role in promoting cell invasion, migration and distant metastasis in HNSCC via pathways other than EMT and that the down-regulation of JunB may become an effective strategy for patients with invasive HNSCC.

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Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis.

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Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis.

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