UNC-45A is a novel microtubule-associated protein and regulator of paclitaxel sensitivity in ovarian cancer cells

UNC-45A, a highly conserved member of the UCS (UNC45A/CRO1/SHE4P) protein family of co-chaperones, plays an important role in regulating cytoskeletal-associated functions in invertebrates and mammalian cells including cytokinesis, exocytosis, cell motility, and neuronal development. Here, for the first time UNC-45A is demonstrated to function as a mitotic-spindle-associated protein that destabilizes microtubules (MTs) activity. Using in vitro biophysical reconstitution and total internal reflection fluorescence (TIRF) microscopy analysis, reveal that UNC-45A directly binds to taxol-stabilized MTs in the absence of any additional cellular co-factors or other microtubule-associated proteins (MAPs) and acts as an ATP-independent microtubule destabilizer. In cells, UNC-45A binds to and destabilizes mitotic spindles and its depletion causes severe defects in chromosome congression and segregation. UNC-45A is overexpressed in human clinical specimens from chemoresistant ovarian cancer and that UNC-45A overexpressing cells resist chromosome mis-segregation and aneuploidy when treated with clinically relevant concentrations of paclitaxel. Lastly, UNC-45A depletion exacerbates paclitaxel-mediated stabilizing effects on mitotic spindles and restores sensitivity to paclitaxel. Implications: These findings reveal novel and significant roles for UNC-45A in regulation of cytoskeletal dynamics, broadening our understanding of the basic mechanisms regulating microtubule stability and human cancer susceptibility to paclitaxel, one of the most widely used chemotherapy agents for the treatment of human cancers.