Editors' ChoiceCancer

Hippo Arrests Tetraploid Cells

Sci. Signal.  26 Aug 2014:
Vol. 7, Issue 340, pp. ec227
DOI: 10.1126/scisignal.2005829

Cancer cells frequently exhibit tetraploidy, a doubling of the genome that can result from defects in cell division that usually should result in cell death. In nontransformed cells, tetraploidy triggers cell cycle arrest through the tumor suppressor protein p53. Ganem et al. found that the Hippo pathway is activated by tetraploidy and promotes p53 stability (see Zhao and Guan). An RNA interference (RNAi) screen in tetraploid RPE1, a retinal epithelial cell line, identified p53, the cell cycle inhibitor protein p21, and the Hippo pathway kinase LATS2 as proteins that restricted proliferation. Loss of LATS2 expression was observed in a small subpopulation of cells that exhibited spontaneous recovery of cell cycling. The abundance of p53 and the phosphorylation of LATS2 and its substrate, the transcriptional regulator Yes-associated protein (YAP), were greater in tetraploid than in diploid RPE1 cells. In the tetraploid cells, the proportion of cells with cytoplasmic YAP was also greater than in diploid cells, and the abundance of the transcriptional coactivator TAZ and the expression of YAP/TAZ target genes were decreased. Overexpression of nonphosphorylatable, but not of wild-type, YAP increased the proliferation of tetraploid cells. Consistent with the known function of LATS2 to inhibit the E3 ubiquitin ligase MDM2, which targets p53 for degradation, knocking down LATS2 decreased the abundance of p53 to an amount similar to that in diploid cells. HA-tagged LATS2 coimmunoprecipitated with endogenous MDM2 in tetraploid but not diploid RPE1 cells. To understand how the Hippo pathway and LATS2 may be activated in tetraploid cells, the authors examined the cells for changes in the cytoskeleton and contractility, which are known to regulate the Hippo pathway. Tetraploid cells exhibited decreased contractile force and had decreased activation of the contractility-associated proteins myosin light chain and RhoA, coincident with increased activation of Rac1, which inhibits RhoA in response to extra centrosomes. Proliferation of tetraploid cells was increased, and the abundance of p53 and phosphorylated LATS2 and YAP was decreased, by activating or overexpressing RhoA or by knocking down or inhibiting Rac1. Inducing extra centrosomes in diploid RPE-1 cells increased LATS2 phosphorylation, as well as YAP phosphorylation and p53 abundance in a LATS2-dependent manner. Hepatocytes in mice spontaneously become tetraploid with age. Knocking out p53 or expressing a liver-specific, constitutively active YAP enhanced the proliferation of tetraploid hepatocytes in vivo. The findings suggest that loss of Hippo signaling in cancer enables the propagation of tetraploid cells.

N. J. Ganem, H. Cornils, S.-Y. Chiu, K. P. O’Rourke, J. Arnaud, D. Yimlamai, M. Théry, F. D. Camargo, D. Pellman, Cytokinesis failure triggers Hippos tumor suppressor pathway activation. Cell 158, 833–848 (2014). [PubMed]

B. Zhao, K.-L. Guan, Hippo pathway key to ploidy checkpoint. Cell 158, 695–696 (2014). [PubMed]

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