Journal
ONCOTARGET
Volume 6, Issue 34, Pages 36019-36031Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5935
Keywords
Hippo-YAP pathway; PDAC; cell motility; LPAR3; mitotic phosphorylation
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Funding
- NCI NIH HHS [CA127297, P50 CA127297, U54 CA163120, P30 CA036727] Funding Source: Medline
- NIGMS NIH HHS [R01 GM109066, P30 GM106397] Funding Source: Medline
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The transcriptional co-activator Yes-associated protein, YAP, is a main effector in the Hippo tumor suppressor pathway. We recently defined a mechanism for positive regulation of YAP through CDK1-mediated mitotic phosphorylation. Here, we show that active YAP promotes pancreatic cancer cell migration, invasion and anchorage-independent growth in a mitotic phosphorylation-dependent manner. Mitotic phosphorylation is essential for YAP-driven tumorigenesis in animals. YAP reduction significantly impairs cell migration and invasion. Immunohistochemistry shows significant upregulation and nuclear localization of YAP in metastases when compared with primary tumors and normal tissue in human. Mitotic phosphorylation of YAP controls a unique transcriptional program in pancreatic cells. Expression profiles reveal LPAR3 (lysophosphatidic acid receptor 3) as a mediator for mitotic phosphorylation-driven pancreatic cell motility and invasion. Together, this work identifies YAP as a novel regulator of pancreatic cancer cell motility, invasion and metastasis, and as a potential therapeutic target for invasive pancreatic cancer.
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