Cyclin A2, Rho GTPases and EMT

Abstract

Cell cycle regulators, such as cyclins, are often upregulated in many proliferative disorders, and Cyclin A2 is generally considered as a marker of aggressive cancers. Our recent work, which revealed decreased expression of Cyclin A2 upon metastasis of colorectal cancer, suggests a more complicated situation. Consistent with this, we identified a role for Cyclin A2, via RhoA, in regulation of the actin cytoskeleton and the control of cell invasion. Cyclin A2 also regulates spindle orientation which, when misoriented, could disrupt cell polarity and favor cancer cell detachment from the tumor as part of a transforming process, such as epithelial to mesenchymal transition (EMT). During EMT, cells undergo morphological and molecular changes toward a mesenchymal phenotype. Upregulation, or increased activity of some Rho GTPases, such as Cdc42, Rac1 or RhoC, increases the invasive potential of these cells. This correlates with the inverse relationship between RhoA and RhoC activities we observed in an epithelial cell type. Altogether, these observations raise the possibility that Cyclin A2 is instrumental in preventing EMT and therefore cancers of epithelial tissues.

Figure 1. Cell cycle regulators and the Rho/ROCK pathway. Whereas Cyclin D1, p27, p21, and p57 collectively define the inhibitory arm of a regulatory loop linking the cell cycle to the RhoA/ROCK pathway, Cyclin A2 appears to be the first component in its activator arm.

Figure 2. Cyclin A2 is at the interface between cytoplasmic and extracellular cues. When Cyclin A2 level is high, the two daughter cells orientate their bipolar mitotic spindles according to both their mother footprint and cues emanating from the lamina. If Cyclin A2 is abnormally downregulated, cell division is non-localized, cell spreading is isotropic and cells show increased motility.