期刊
MOLECULAR CANCER RESEARCH
卷 18, 期 10, 页码 1574-1588出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-20-0165
关键词
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资金
- Department of Defense Career Development Grant [W81XWH-18-1-0297]
- National Institute of Diabetes and Digestive and Kidney Diseases of the NIH [T32DK07198]
- National Cancer Institute [K08CA236874]
- Optical Microscopy Core services through the Mayo Clinic Center for Cell Signaling in Gastroenterology [P30DK084567]
- Mayo Clinic Medical Genome Facility -Proteomics Core
- Mayo Clinic Hepatobiliary SPORE from the NCI [P50 CA210964]
- Mayo Clinic Department of Surgery
- Mayo Clinic
The Hippo pathway effector Yes-associated protein (YAP) is localized to the nucleus and transcriptionally active in a number of tumor types, including a majority of human cholangiocarcinomas. YAP activity has been linked to chemotherapy resistance and has been shown to rescue KRAS and BRAF inhibition in RAS/RAF-driven cancers; however, the underlying mechanisms of YAP-mediated chemoresistance have yet to be elucidated. Herein, we report that the tyrosine phosphatase SHP2 directly regulates the activity of YAP by dephosphorylating pYAP(Y357) even in the setting of RAS/RAF mutations, and that diminished SHP2 phosphatase activity is associated with chemoresistance in cholangiocarcinomas. A screen for YAP-interacting tyrosine phosphatases identified SHP2, and characterization of cholangiocarcinomas cell lines demonstrated an inverse relationship between SHP2 levels and pYAP(Y357). Human sequencing data demonstrated lower SHP2 levels in cholangiocarcinomas tumors as compared with normal liver. Cell lines with low SHP2 expression and higher levels of pYAP(Y357) were resistant to gemcitabine and cisplatin. In cholangiocarcinomas cells with high levels of SHP2, pharmacologic inhibition or genetic deletion of SHP2 increased YAP(Y357) phosphorylation and expression of YAP target genes, including the antiapoptotic regulator MCL1, imparting resistance to gemcitabine and cisplatin. In vivo evaluation of chemotherapy sensitivity demonstrated significant resistance in xenografts with genetic deletion of SHP2, which could be overcome by utilizing an MCL1 inhibitor.
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