YAP in pancreatic cancer: oncogenic role and therapeutic strategy

Abstract

Pancreatic cancer, especially pancreatic ductal adenocarcinoma (PDAC), remains a fatal disease with few efficacious treatments. The Hippo signaling pathway, an evolutionarily conserved signaling module, plays critical roles in tissue homeostasis, organ size control and tumorigenesis. The transcriptional coactivator yes-associated protein (YAP), a major downstream effector of the Hippo pathway, is associated with various human cancers including PDAC. Considering its importance in cancer, YAP is emerging as a promising therapeutic target. In this review, we summarize the current understanding of the oncogenic role and regulatory mechanism of YAP in PDAC, and the potential therapeutic strategies targeting YAP.

Keywords: Hippo pathway; KRAS; Pancreatic cancer; YAP; therapeutic target.

Figure 1

Core components of the Hippo pathway in mammalian cells. The core components of Hippo pathway consist of MST1/2, LATS1/2 and YAP/TAZ. When the Hippo pathway is ON, MST1/2, in complex with SAV1, phosphorylate LATS1/2 and MOB1. MAP4Ks also phosphorylate and activate LATS1/2. NF2 is an additional and potent activator of LATS1/2 that is devoid of kinase activity. Activated LATS1/2 phosphorylate YAP and TAZ, resulting in 14-3-3-mediated YAP/TAZ cytoplasmic retention and ubiquitin-mediated proteasomal degradation. When the Hippo pathway is OFF, YAP/TAZ are dephosphorylated and translocate to the nucleus, where they compete with VGLL4 for TEADs binding and induce the transcription of downstream target genes, such as CTGF and CYR61, which are involved in growth, proliferation, and survival.

Figure 2

Schematic illustration of the posttranslational modifications of YAP. In addition to phosphorylation and ubiquitylation, YAP can also be regulated by several other posttranslational modifications including high glucose-stimulated YAP O-GlcNAcylation for increasing YAP stability, SIRT1-mediated YAP deacetylation for enhancing YAP/TEAD association, SETD7 methylated methylation for YAP cytoplasmic retention, and SET1A-mediated methylation for YAP nuclear retention.

Figure 3

Schematic overview of YAP functions in pancreatic cancer. YAP exerts oncogenic functions in different aspects of PDAC, including proliferation, survival, metastasis, metabolic reprogramming, and cancer stem cells, as well as inflammation and immunosuppression.

Figure 4

Regulation of YAP in PDAC. Multiple signals are integrated to regulate YAP activity. Soluble factors binding to GPCRs regulate LATS kinase through Rho. The insulin/IGF-1 receptor contributes to YAP activation through PI3K. WNT stimulation diverts YAP away from the β‑catenin destruction complex. TGF-β facilitates YAP nuclear translocation through RASSF1A. Other factors also affect YAP activity, in Hippo dependent or independent manners.

Figure 5

Targeting YAP for PDAC therapy. There are several strategies for targeting YAP in PDAC. Statin-mediated inhibition of HMG-CoA reductase in the mevalonate pathway reduces the geranylgeranylation and membrane localization of Rho GTPases, restricting YAP nuclear accumulation and thus its activity. Verteporfin and VGLL4-mimicking peptides disrupt the interaction between YAP and TEAD, inhibiting YAP-induced transcription. Metformin activates AMPK, which inhibits YAP both directly and by activating LATS kinases. BET inhibitors oppose the transcription of YAP-regulated genes. Neratinib increases the phosphorylation of LATS1 and YAP, causing YAP cytosolic accumulation and degradation.