UNC-45A is a Novel Microtubule Destabilizing Protein and Regulator of Paclitaxel Sensitivity in Ovarian Cancer

Abstract

UNC-45A is a highly-conserved member of the UCS protein family that has important roles in regulating cytoskeletal-associated functions in invertebrates and mammalian cells including cytokinesis, exocytosis, cell motility, and neuronal development. Here we show for the first time that UNC-45A is a microtubule-associated protein (MAP) with microtubule (MT) destabilizing activity. Using in vitro biophysical reconstitution and TIRF microscopy analysis, we show that UNC-45A directly binds to taxol-stabilized microtubules in absence of any additional cellular cofactors and acts as an ATP-independent microtubule destabilizer. In cells, we show that UNC-45A binds to and destabilizes microtubules and its depletion causes severe defects in chromosome congression, segregation, and spindle polarity. We also show that UNC-45A is overexpressed in human specimens of chemoresistant ovarian cancer and that UNC-45A overexpressing, chemoresistant cells resist chromosome mis-segregation and aneuploidy when treated with clinically relevant concentrations of paclitaxel. Lastly, we show that UNC-45A depletion exacerbates paclitaxel-mediated stabilizing effects on mitotic spindles and increases sensitivity to paclitaxel. Taken together, our studies support the role of UNC-45A as a novel member of the MT destabilizing protein family and as a molecular target for paclitaxel-resistant human cancers.