Cancer cells often have unstable genomes and increased centrosome and chromosome numbers, which are an important part of malignant transformation in the most recent model of
tumorigenesis. However, very little is known about divisional failures in
cancer cells that may lead to chromosomal and centrosomal amplifications. In this study, we show that
cancer cells often failed at cytokinesis because of 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 markedly reduced, resulting in enhanced genome stabilization. Furthermore, both overexpression of
myosin phosphatase or inhibition of the
myosin light-chain kinase in nonmalignant cells could recapitulate some of the mitotic defects of
cancer cells, including multinucleation and multipolar spindles, indicating that 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.