Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition

Endothelial cell (EC) plasticity in pathological settings has recently been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here, we found that combined knockdown of two ETS family transcription factors, ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG and FLI1 are critical transcriptional activators for EC-specific genes, among which microRNA-126 partially contributes to blocking the induction of EndMT. Moreover, we demonstrated that ERG and FLI1 expression is downregulated in ECs within tumors by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in ECs, and EC behavior in pathological conditions.
Author summary Differentiated cells possess unique characteristics to maintain vital activities. However, cells occasionally show abnormal behavior in pathological settings due to dysregulated gene expression. Endothelial-to-mesenchymal transition (EndMT) is a phenomenon in which endothelial cells lose their characteristics and acquire mesenchymal-like properties. Although EndMT is observed in various diseases including cancer, and augments fibrosis and vascular defects, the mechanism of EndMT induction is not fully understood. Here, we show that EndMT is triggered via reduced expression of ERG and FLI1, which have recently been recognized as pivotal transcription factors in endothelial cells (ECs). Mechanistically, ERG and FLI1 activate EC-specific genes and repress mesenchymal-like genes via epigenetic regulation to prevent EndMT. Furthermore, we demonstrate that microRNA-126, which is specifically expressed in ECs, is the key downstream target of ERG/FLI1 for regulating EndMT. Finally, we show that ERG and FLI1 expression is decreased in ECs within tumors, suggesting that EndMT is induced in the tumor microenvironment. Collectively, these findings indicate that loss of ERG and FLI1 leads to the aberrant behavior of ECs in pathological conditions.