Abstract
Endothelial-to-mesenchymal transition (EndMT) contributes to the pathogenesis of a host of human diseases. RhoJ, a small G protein, is abundantly expressed in endothelial cells. In the present study, we investigated the potential role RhoJ plays in EndMT. We report that RhoJ depletion by small interfering RNA attenuated hypoxia induced EndMT in both immortalized endothelial cells and human primary microvascular endothelial cells. RhoJ knockdown blocked the recruitment of TWIST and SNAIL, two transcriptional repressors, to the promoter region of VE-CADHERIN, a prominent endothelial marker. RhoJ mediated the induction of TWIST and SNAIL expression, under hypoxic conditions, by promoting the binding of HIF-1α to the gene promoters and by enhancing the accumulation of trimethylated histone H3K4. Further analysis revealed that RhoJ was essential for the up-regulation of WDR5, a key component of the mammalian H3K4 methyltransferase, by hypoxia thereby leading to the trans-activation of TWIST and SNAIL. Finally, lentivirus mediated over-expression of WDR5 compensated for the loss of TWIST and SNAIL and allowed EndMT to proceed despite the absence of RhoJ in hypoxia-challenged endothelial cells. In conclusion, we propose that RhoJ-dependent induction of WDR5 may be essential for hypoxia-induced EndMT.