Mst1 and Mst2 Maintain Hepatocyte Quiescence and Suppress Hepatocellular Carcinoma Development through Inactivation of the Yap1 Oncogene

Abstract

Hippo-Lats-Yorkie signaling regulates tissue overgrowth and tumorigenesis in Drosophila. We show that the Mst1 and Mst2 protein kinases, the mammalian Hippo orthologs, are cleaved and constitutively activated in the mouse liver. Combined Mst1/2 deficiency in the liver results in loss of inhibitory Ser127 phosphorylation of the Yorkie ortholog, Yap1, massive overgrowth, and hepatocellular carcinoma (HCC). Reexpression of Mst1 in HCC-derived cell lines promotes Yap1 Ser127 phosphorylation and inactivation, and abrogates their tumorigenicity. Notably, Mst1/2 inactivates Yap1 in liver through an intermediary kinase distinct from Lats1/2. Approximately 30% of human HCCs show low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved, activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in liver relevant to human HCC. Significance The pathways that regulate quiescence and tumor suppression in the liver have not been fully elucidated. We show that the Mst1 and Mst2 kinases are tumor suppressors and regulators of liver size in adults and that negative regulation of the transcriptional coactivator, Yap1, is central to Mst1/2 tumor suppressor function. Loss of both Mst1 and Mst2 is sufficient to initiate hepatocyte proliferation, resulting in dramatic liver overgrowth, resistance to pro-apoptotic stimuli, and the development of HCC. Mst1 and Mst2 promote phosphorylation of Yap1 and thereby suppress its oncogenic activity. Mst1/2 regulation of Yap1 is tissue-specific and, in the liver, involves an Mst1/2-regulated Yap1 kinase distinct from Lats1/2. Significantly, the Mst-Yap1 pathway is disrupted in a substantial fraction of human HCCs.