Loss of Hippo Signaling Promotes Polyploidy and Tumorigenesis

Polyploidy can lead to genomic instability, aneuploidy, and tumorigenesis when polyploid cells do not undergo G1 arrest. Hippo signaling is highly active in polyploid cells, and overexpression of its downstream effector YAP increases hepatocyte polyploidy. However, the mechanisms by which Hippo signaling contributes to polyploidy have not been determined. Zhang, Chen, Liu, and colleagues found that YAP activation in response to loss of Hippo signaling promoted hepatocyte polyploidy in mice and synergized with p53 inactivation to induce liver tumorigenesis. Mechanistically, YAP activation induced AKT signaling that resulted in p300-mediated acetylation of the E3 ligase SKP2, promoting its cytoplasmic retention. Nuclear SKP2 targets the cyclin-dependent kinase inhibitor p27 for degradation; thus, cytoplasmic retention of SKP2 stabilized p27, preventing cell-cycle progression. In contrast, cytoplasmic SKP2 targets the proapoptotic FOXO1 and FOXO3 proteins for degradation. Consequently, YAP activation promoted FOXO1/3 degradation to enhance polyploid cell proliferation. These findings reveal a role for AKT–SKP2 signaling in inducing mitotic arrest and polyploidy, demonstrating a mechanism by which loss of Hippo signaling can enhance polyploidy and tumorigenesis. Consistent with these findings, inhibition or depletion of AKT reduced p27 levels, decreased cell polyploidy, and suppressed liver tumor formation in mice with disrupted Hippo signaling. Treatment with the AKT inhibitor MK2206 reduced tumor size and frequency, and was associated with reduced levels of cytoplasmic SKP2. In human liver tumors, YAP and SKP2 were highly expressed compared to adjacent normal tissue, and YAP and SKP2 levels were associated with advanced tumor stage. Additionally, low levels of nuclear YAP were associated with improved survival in patients with hepatocellular carcinoma. Together, these findings reveal a mechanism by which Hippo signaling may suppress polyploidy and tumorigenesis, and suggest that AKT may be a potential therapeutic target in patients with hepatocellular carcinoma.

Zhang S, Chen Q, Liu Q, Li Y, Sun X, Hong L, et al. Hippo signaling suppresses cell ploidy and tumorigenesis through Skp2. Cancer Cell 2017;31:669–84.e7.

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