Tetraploidy Activates the Hippo Tumor Suppressor Pathway

Defects in mitosis or cytokinesis generate genetically unstable tetraploid cells, which may contribute to tumorigenesis and have been detected in numerous tumors. The proliferation of these cells is limited by p53-mediated cell-cycle arrest; however, the mechanisms underlying p53 activation in tetraploid cells are unknown. To address this question, Ganem, Cornils, and colleagues performed a genome-wide RNAi screen in tetraploid cells generated by induction of cytokinesis failure. This approach identified 98 proteins whose silencing enabled tetraploid cells to bypass p53-driven G₁ arrest, including many negative regulators of growth factor signaling. Depletion of large tumor suppressor kinase 2 (LATS2), a core component of the Hippo tumor suppressor pathway, increased tetraploid cell proliferation. Tetraploidy induced LATS2 activation, resulting in phosphorylation and inactivation of the transcriptional coactivators YAP and TAZ and stabilization of p53 via LATS2 interaction with MDM2. LATS2 activation was mediated, in part, by the presence of extra centrosomes in tetraploid cells, which stimulated hyperactivation of the small G protein RAC1 and antagonized RHOA activity. Expression of constitutively active YAP, reactivation of RHOA, or attenuation of RAC activity in tetraploid cells was sufficient to overcome the Hippo pathway–dependent proliferative barrier. In vivo studies revealed that activation of the Hippo pathway suppressed the growth of naturally occurring tetraploid hepatocytes in a p53-dependent manner. Furthermore, in vitro evolution studies confirmed that the Hippo pathway was inactivated in proliferating tetraploid cells, as were many genes identified in the RNAi screen. These findings reveal a role for the Hippo pathway in suppressing the oncogenic potential of tetraploid cells and provide insight into how tumor cells can bypass Hippo-mediated growth inhibition.

Ganem NJ, Cornils H, Chiu SY, O'Rourke KP, Arnaud J, Yimlamai D, et al. Cytokinesis failure triggers Hippo tumor suppressor pathway activation. Cell 2014;158:833–48.

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