title: 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.
authors: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Xiangming
authors: X
authors: Ding
authors: Hongya
authors: H
authors: Pan
authors: Jiong
authors: J
authors: Li
authors: Qi
authors: Q
authors: Zhong
authors: Xiaohong
authors: X
authors: Chen
authors: Sarah M
authors: SM
authors: Dry
authors: Cun-Yu
authors: CY
authors: Wang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D000099169:Fos-Related Antigen 1
chemical_list: D056484:Jumonji Domain-Containing Histone Demethylases; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C494424:KDM4A protein, human
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