Research ArticleCancer

Epigenetic Activation of AP1 Promotes Squamous Cell Carcinoma Metastasis

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Science Signaling  30 Apr 2013:
Vol. 6, Issue 273, pp. ra28
DOI: 10.1126/scisignal.2003884

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Targeting Metastasis

Gene expression can be affected not only by mutations in a gene but also by epigenetic changes, such as histone methylation status. Ding et al. found that histone methylation by KDM4A was important in mediating a positive feedback loop in squamous cell carcinoma (SCC) that enabled the transcription factor complex AP1 (activating protein 1) to induce the expression of its component transcription factors, JUN and FOSL1, implicated in metastatic cancer. Depletion of KDM4A suppressed invasion by SCC cells in vitro and decreased the incidence of lymph node metastasis of SCC tumors in a mouse cancer model. The abundance of KDM4A correlated with that of JUN and FOSL1 in human primary SCC and metastatic SCC tissue. The findings suggest that KDM4A could be targeted to prevent metastasis of SCC.


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.

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