Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is generally a fatal disease with no efficacious treatment modalities. Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed. Here, we review the role of Yes-associated protein (YAP) and WW-domain-containing Transcriptional co-Activator with a PDZ-binding motif (TAZ) in the development of PDAC. These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes. We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database (www.proteinatlas.org/pathology) that allows genome-wide exploration of the impact of individual proteins on survival outcomes. Multiple YAP/TEAD-regulated genes, including AJUBA, ANLN, AREG, ARHGAP29, AURKA, BUB1, CCND1, CDK6, CXCL5, EDN2, DKK1, FOSL1,FOXM1, HBEGF, IGFBP2, JAG1, NOTCH2, RHAMM, RRM2, SERP1, and ZWILCH, are associated with unfavorable survival of PDAC patients. Similarly, components of AP-1 that synergize with YAP (FOSL1), growth factors (TGFα, EPEG, and HBEGF), a specific integrin (ITGA2), heptahelical receptors (P2Y2R, GPR87) and an inhibitor of the Hippo pathway (MUC1), all of which stimulate YAP activity, are associated with unfavorable survival of PDAC patients. By contrast, YAP inhibitory pathways (STRAD/LKB-1/AMPK, PKA/LATS, and TSC/mTORC1) indicate a favorable prognosis. These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients. We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease.

TGFβ and Hippo Pathways Cooperate to Enhance Sarcomagenesis and Metastasis through the Hyaluronan-Mediated Motility Receptor (HMMR)

“…We also sought evidence that these pathways converge to regulate metastasis. The hyaluronan-mediated motility receptor (HMMR) gene (14), which encodes the hyaluronic acid (HA) surface receptor RHAMM, is a known transcriptional target of TGFb signaling (15) and has recently been linked to YAP1 (16,17). RHAMM is also associated with fibrosarcoma progression (18).…”

YAP Activity is Not Associated with Survival of Uveal Melanoma Patients and Cell Lines

“…In addition, hyperactive YAP is known to be important for metastasis or the acquisition of resistance to anticancer agents [16][17][18][19] . YAP mRNA expression levels and YAP-regulated molecular signatures have been shown to be prognostic factors in the survival of patients with pancreatic ductal adenocarcinoma and those with oral squamous cell carcinoma, respectively [20][21][22] . Immunohistochemical nuclear YAP staining has also been reported as a significant prognostic factor in adenocarcinomas of the ampulla of Vater 23 .…”

RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1

“…Hippo signaling is tightly regulated by MST1/2 and LATS1/2, which phosphorylates the YAP-1 at Ser127 (Hippo on) resulting in its cytoplasmic retention and proteasome-mediated degradation. Similarly, phosphorylation at Ser397 of YAP-1 by LATS1/2 creates a phospho□degron motif for β□TrCP binding followed by proteasomal degradation [13]. We did not find any increase in phosphorylated YAP-1, rather, lower expression of p-YAP (at Ser-127 and Ser-397) were observed in RRBP1 KO as compared to WT cells (Figure 4D).…”

“…Recently, Hippo signaling has also been correlated to mediate chemoresistance in different neoplasms to several chemotherapeutic drugs [31]. Similarly, phosphorylation at S397 of YAP-1 by LATS1/2 creates a phospho□degron motif for β□TrCP binding followed by proteasomal degradation [13]. Overall, dephosphorylated YAP-1 (Hippo off) translocate to the nucleus to transcribe the YAP-1 target genes.…”