MEF2D Transduces Microenvironment Stimuli to ZEB1 to Promote Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.

Epithelial-mesenchymal transition (EMT) is an essential mechanism of metastasis, including in colorectal cancer. Although EMT processes are often triggered in cancer cells by their surrounding microenvironment, how EMT-relevant genes control these processes is not well understood. In multiple types of cancers, the transcription factor MEF2D has been implicated in cell proliferation, but its contributions to metastasis have not been addressed. Here, we show MEF2D is overexpressed in clinical colorectal cancer tissues where its high expression correlates with metastatic process. Functional investigations showed that MEF2D promoted cancer cell invasion and EMT and that it was essential for certain microenvironment signals to induce EMT and metastasis in vivo Mechanistically, MEF2D directly regulated transcription of the EMT driver gene ZEB1 and facilitated histone acetylation at the ZEB1 promoter. More importantly, MEF2D responded to various tumor microenvironment signals and acted as a central integrator transducing multiple signals to activate ZEB1 transcription. Overall, our results define a critical function for MEF2D in upregulating EMT and the metastatic capacity of colorectal cancer cells. Further, they offer new insights into how microenvironment signals activate EMT-relevant genes and deepen the pathophysiologic significance of MEF2D, with potential implications for the prevention and treatment of metastatic colorectal cancer. Cancer Res; 76(17); 5054-67. ©2016 AACR. ©2016 American Association for Cancer Research.