MKL1 links epigenetic activation of MMP2 to ovarian cancer cell migration and invasion.

Responding to pro-metastatic cues such as low oxygen tension, cancer cells develop several different strategies to facilitate migration and invasion. During this process, expression levels of matrix metalloproteinases (MMPs) are up-regulated so that cancer cells can more easily enter or exit the circulation. In this report we show that message levels of the transcriptional modulator MKL1 were elevated in malignant forms of ovarian cancer tissues in humans when compared to more benign forms accompanying a similar change in MMP2 expression. MKL1 silencing blocked hypoxia-induced migration and invasion of ovarian cancer cells (SKOV-3) in vitro. Over-expression of MKL1 activated while MKL1 depletion repressed MMP2 transcription in SKOV-3 cells. MKL1 was recruited to the MMP2 promoter by NF-κB in response to hypoxia. Mechanistically, MKL1 recruited a histone methyltransferase, SET1, and a chromatin remodeling protein, BRG1, and coordinated their interaction to alter the chromatin structure surrounding the MMP2 promoter leading to transcriptional activation. Both BRG1 and SET1 were essential for hypoxia-induced MMP2 trans-activation. Finally, expression levels of SET1 and BRG1 were positively correlated with ovarian cancer malignancies in humans. Together, our data suggest that MKL1 promotes ovarian cancer cell migration and invasion by epigenetically activating MMP2 transcription.