MLL regulates actin cytoskeleton and cell migration by stabilizing Rho GTPases via the transcription of RhoGDI1

Attainment of proper cell shape and regulation of cell migration are essential processes in development of an organism. Mixed lineage leukemia (MLL) protein, a H3K4 histone methyltransferase, plays critical role in cell-fate decisions during skeletal development and haematopoiesis in higher vertebrates. Rho GTPases—RhoA, Rac1 and CDC42—are small G proteins that regulate various key cellular processes like actin cytoskeleton formation, maintenance of cell shape, and cell migration etc. Here we report that MLL regulates the homeostasis of these small Rho GTPase. Loss of MLL results in abnormal cell shape and disrupted actin cytoskeleton, that leads to diminished cell spreading and migration. MLL depletion affects the stability and activity of Rho GTPases in SET domain-dependent manner, but these Rho GTPases are not direct transcriptional targets of MLL. Instead, MLL regulates the transcript levels of their chaperone protein RhoGDI1. Using MDA-MB-231, a triple negative breast cancer cell line with high RhoGDI1 expression, we show that MLL depletion or inhibition by small molecule reduces tumour progression in nude mice. Our studies highlight the central regulatory role of MLL in Rho/Rac/CDC42 signalling pathways.