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Squamous cell carcinoma (SCC) of the oral cavity, head and neck is one of the most deadly and debilitating diseases worldwide with a 5-year survival rate of only ～50％.The poor prognosis of patients with SCC mainly is due to the high invasive growth potential of these tumors, resulting in regional lymph node metastasis1-3.However, the molecular and epigenetic mechanisms which control SCC metastasis are poorly understood.Using a functional siRNA screen,we identified that the histone demethylase KDM4A played a critical role in the invasive growth and metastasis of SCC mediated by the Oncogenic MET.Mechanistically, KDM4A promoted SCC metastasis by controlling AP1 activation.KDM4A facilitated JUN/AP1 binding to chromatin to induce the expression of FOSL1 and JUN by erasing H3K9me3 and H3K36me3 marks.An orthotopic mouse model revealed that the depletion of KDM4A significantly inhibited SCC lymph node metastasis.Moreover, immunostaining demonstrated that the levels of KDM4A were correlated with the expression of JUN and FOSL1 in human SCC tissues, and that KDM4A was highly expressed in human lymph node metastasis.Our studies provide novel insights into the epigenetic control of human SCC metastasis, and suggest that KDM4A is a key therapeutic target for inhibiting invasive SCC growth and preventing metastasis.