MED12 exerts an emerging role in actin-mediated cytokinesis via LIMK2/Cofilin pathway in non-small cell lung cancer. MED12

Mediator complex subunit 12 (MED12), a key component of RNA polymerase II transcriptional complex, is frequently mutated in human tumors, yet little is known about how it controls tumor progression. Here we uncovered a crucial and unprecedented function of MED12 in regulating cytokinesis in non-small cell lung cancer (NSCLC) cells. MED12 deletion led to aborted cytokinesis of NSCLC cells via upregulating LIMK2 and further accelerating its phosphorylation. Activated LIMK2 directly phosphorylated and inactivated cofilin, which caused robust actin reorganization and further disrupted the balance of actin polymerization and depolymerization. Disorganized actin filaments impeded the normal abscission process in the late cytokinesis stages, resulting in the failure of cytokinesis and multinucleation which eventually contributed to the decrease of cell proliferation in vitro cell culture and in vivo mouse xenografts. Furthermore, disorganization of actin dynamics and multinucleation as well as decreased cell proliferation could be partly restored via ectopic expression of MED12. Importantly, clinical data showed that higher MED12 expression was a common event in NSCLC, which was strongly correlated with larger tumor volume and adverse patient survival. Thus, we identified MED12 as an important regulator for maintaining accurate cytokinesis and uncovered the LIMK2/cofilin pathway as a potential therapeutic target for NSCLC