Despite its frequent inactivation in human breast cancers, the role of p21(Cip1) (p21) in morphological plasticity of normal mammary epithelial cells is still poorly understood. To address this question, we have investigated the consequences of p21 silencing in two-dimensional (2D) morphogenesis of untransformed human mammary epithelial cells. Here we show that p21 inactivation causes a reduction of 2D cell spreading and suppresses focal adhesion. In order to investigate the cytoskeletal modifications associated with this altered morphology, we have analyzed the microtubule dynamics in interphase p21-depleted cells. Our results demonstrate that interphase microtubule dynamic instability is strongly increased by p21 silencing. This alteration correlates with severe microtubule hypoacetylation. Next, we show that these microtubule defects in p21-depleted cells can be reversed by the use of the small molecule tubacin, a specific inhibitor of the α-tubulin deacetylase HDAC6. Tubacin-induced microtubule dynamics decrease also correlates with a partial recovery of cell spreading and focal adhesion in those cells. Collectively, these data indicate that p21 regulates the morphological plasticity of normal mammary epithelial cells by modulating dynamics of key cytoskeletal components.
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