Study on the role of YAP/TAZ as oncogenic drivers in gastric cancer

Abstract

Hippo pathway effectors YAP and TAZ are known to play important roles in gastric cancer. However, it remains elusive whether activation of these oncogenes are sufficient to drive carcinogenesis. Here, we show that activation of YAP/TAZ by knockouts of Lats1 and Lats2 in pyloric stem cells cause step-wise carcinogenesis in vivo. Through RNA sequencing, we identified MYC as a decisive target of YAP, which controls MYC at the transcriptional and post-transcriptional levels. These mechanisms tightly regulated MYC in homeostatic conditions, but YAP activation altered this balance by impeding miRNA processing, causing a shift towards MYC upregulation. Pharmacological inhibition of MYC suppressed YAP-dependent phenotypes both in vitro and in vivo. Human gastric cancer samples also displayed a significant correlation between YAP and MYC. We re-analyzed human transcriptome data to verify enrichment of YAP signatures in a subpopulation of gastric cancers and found that our model closely reflected the molecular pattern of patients with high YAP activity. In conclusion, we provide genetic evidence of YAP/TAZ as oncogenic initiators and drivers for gastric cancer and verify MYC as the key downstream mediator of YAP in carcinogenesis. These findings are also evident in human gastric cancer, emphasizing the significance of YAP/TAZ signaling in gastric carcinogenesis.