The YAP-Interacting Phosphatase SHP2 Can Regulate Transcriptional Coactivity and Modulate Sensitivity to Chemotherapy in Cholangiocarcinoma

Abstract

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 (CCA). 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 CCA. A screen for YAP interacting tyrosine phosphatases identified SHP2, and characterization of CCA cell lines demonstrated an inverse relationship between SHP2 levels and pYAP Y357 . Human sequencing data demonstrated lower SHP2 levels in CCA tumors as compared to normal liver. Cell lines with low SHP2 expression and higher levels of pYAP Y357 were resistant to gemcitabine and cisplatin. In CCA 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 utilizing an MCL1 inhibitor.

Control of Oxidative Stress in Cancer Chemoresistance: Spotlight on Nrf2 Role

“…The involvement in chemoresistance of YAP has also been demonstrated by Bauzone et al, who found a crosstalk between YAP and retinoic acid (RAR)–retinoid X receptor (RXR), which promoted 5-fluorouracil resistance and self-renewal in colorectal cancer cells [ 135 ]. Analogously, the interaction between phosphatase SHP2 and YAP was involved in the chemoresistance of cholangiocarcinoma cell lines [ 136 ]. Moreover, Santoro et al found that the YAP expression was suppressed, and the malignancy and treatment resistance of pancreatic cancer cells were reduced, after inhibition of glycogen synthase kinase (GSK3) [ 137 ].…”

Intra-articular Injection of SHP2 Inhibitor SHP099 Promotes the Repair of Rabbit Full-thickness Cartilage Defect

“…In a previous study focusing on cholangiocarcinoma, SHP2 mediated its chemosensitivity via upregulating YAP activity (23), which could decrease the degradation of β-catenin by regulating para bromin (24). Excessive activation of YAP inhibits the differentiation and maturation of cartilage (12,25).…”

The hippo pathway: A master regulator of liver metabolism, regeneration, and disease

“…254,256 YAP activation in CCA leads to increased cancer cell growth, xenograft tumor growth, and resistance to treatment. 248,251,[254][255][256][257] YAP, binding to TEAD transcription factor, inhibits the pro-death protein TRAIL and activates the pro-angiogenic protein MFAP5. 251 Another YAP target gene in CCA was identified in several tumor cell lines, including CCA cell line HUCCT-1, and models as NUAK2, that negatively modulates LATS, and activates YAP.…”

“…YAP activation in CCA leads to increased cancer cell growth, xenograft tumor growth, and resistance to treatment 248,251,254‐257 . YAP, binding to TEAD transcription factor, inhibits the pro‐death protein TRAIL and activates the pro‐angiogenic protein MFAP5 251 .…”