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Malignant tumors are exemplified by excessive proliferation and aggressive migration/invasion contributing to increased mortality of cancer patients.Matrix metalloproteinase 9 (MMP9) expression is positively correlated with lung cancer malignancy.The mechanism underlying elevated MMP9 expression is not clearly defined.We demonstrate here that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) was activated by hypoxia and TGF-, two prominent pro-malignancy factors, in cultured lung cancer cells.MKL1 levels were also increased in more-invasive types of lung cancer in humans.Depletion of MKL1 in lung cancer cells attenuated migration and invasion both in vitro and in vivo.Over-expression of MKL1 potentiated induction of MMP9 transcription by hypoxia and TGF-while MKL1 silencing diminished MMP9 expression.Of interest, MKL1 knockdown eliminated histone H3K4 methylation surrounding the MMP9 promoter.Further analyses revealed that MKL1 recruited ASH2, a component of H3K4 methyltransferase complex, to activate MMP9 transcription.Depletion of ASH2 meliorated cancer cell migration and invasion in a MMP9-dependent manner.Together, our data indicate that MKL1 potentiates lung cancer cell migration and invasion by epigenetically activating MMP9 transcription.