Deficiency in myosin light-chain phosphorylation causes cytokinesis failure and multipolarity in cancer cells

Abstract

Cancer cells often have unstable genomes and increased centrosome and chromosome numbers, which play an important part of malignant transformation in the most recent models tumorigenesis. However, very little is known about divisional failures in cancer cells that may lead to chromosomal and centrosomal amplifications. We show here that cancer cells often failed at cytokinesis due to decreased phosphorylation of the myosin regulatory light chain (MLC), a key regulatory component of cortical contraction during division. Reduced MLC phosphorylation was associated with high expression of myosin phosphatase and/or reduced myosin light chain kinase levels. Furthermore, expression of phosphomimetic MLC largely prevented cytokinesis failure in the tested cancer cells. When myosin light chain phosphorylation was restored to normal levels by phosphatase knockdown multinucleation, and multipolar mitosis were both markedly reduced, resulting in enhanced genome stabilization. Furthermore, both overexpression of myosin phosphatase or inhibition of the myosin light chain kinase (MLCK) in nonmalignant cells can recapitulate some of the mitotic defects of cancer cells, including multinucleation and multipolar spindles, indicating these changes are sufficient to reproduce the cytokinesis failures we see in cancer cells. These results for the first time define the molecular defects leading to divisional failure in cancer cells.