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Sci. Signal., 30 April 2013
Vol. 6, Issue 273, p. ra28
[DOI: 10.1126/scisignal.2003884]

RESEARCH ARTICLES

Epigenetic Activation of AP1 Promotes Squamous Cell Carcinoma Metastasis

Xiangming Ding1*, Hongya Pan1,2*, Jiong Li1, Qi Zhong1,3, Xiaohong Chen1,3, Sarah M. Dry4,5, and Cun-Yu Wang1,4,6,7{dagger}

1 Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2 Department of Oral and Maxillofacial Surgery, Shanghai Ninth Hospital, Shanghai Jiaotong University, Shanghai 200011, China.
3 Department of Otolaryngology Head and Neck Surgery, Affiliated Beijing Tongren Hospital, Capital University of Medical Sciences, Beijing 100730, China.
4 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5 Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6 Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA.
7 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.

* These authors contributed equally to this work.

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.

{dagger} Corresponding author. E-mail: cunywang{at}ucla.edu

Citation: X. Ding, H. Pan, J. Li, Q. Zhong, X. Chen, S. M. Dry, C.-Y. Wang, Epigenetic Activation of AP1 Promotes Squamous Cell Carcinoma Metastasis. Sci. Signal. 6, ra28 (2013).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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