Prostaglandin $E_2$ and YAP form a positive feedback loop that promotes colon regeneration and tumorigenesis

Abstract

Prostaglandin $E_2 (PGE_2)$ is a key inflammatory mediator governing tissue regeneration, but its chronic activation can also trigger carcinogenesis. Despite its importance, the downstream effectors of $PGE_2$ have remained unclear. Here we show that Yes-associated protein (YAP), a downstream transcriptional co-activator of the Hippo pathway, mediates and amplifies $PGE_2$ function both during tumorigenesis and during regeneration following colitis. $PGE_2$ -induced phosphorylation of CREB transcriptionally activates YAP, which in turn transcriptionally activates cyclooxygenase 2 (COX-2) and EP4, thereby completing a positive feedback loop connecting $PGE_2$ and YAP. Interrupting this loop by YAP gene deletion increases the severity of DSS induced colitis and antagonizes the ability to reverse colitis through manipulations to in-crease colon $PGE_2$ (e.g. genetic ablation of 15-PGDH). Conversely, genetic activation of YAP (by Sav1 gene knockout) synergizes with 15-PGDH gene knock out and in combination induces colon tumors in mice, with tumor development strictly dependent on both intact activity of YAP and of cyclooxygenase. Finally, $PGE_2$ and YAP levels are positively correlated in both sporadic human colon cancers and in human colitis-associated cancers. Our findings thus identify a key role of YAP in amplifying and transducing $PGE_2$ signaling in colon repair and in colon tumorigenesis.