Regulation of the Hippo/YAP signaling pathway in pancreatic cancer by the deubiquitinase POH1

The Hippo signaling pathway, crucial for controlling organ size and tissue regeneration, is evolutionarily conserved and often dysregulated in various cancers, such as pancreatic cancer. Despite the intact inhibition phospho-cascade, the physiological regulation of the Hippo pathway leaves the hyperactivity of the Hippo/YAP axis in pancreatic cancer unexplained. Research indicates that post-translational modifications of YAP are crucial for Hippo pathway activation and cancer progression. Recognizing the role of ubiquitination and deubiquitination in YAP protein stability, we screened a deubiquitinase (DUB) library in pancreatic cancer cells, identifying Pad-one-homologue 1 (POH1) as a key DUB influencing the Hippo pathway and pancreatic cancer progression. Inhibition of the deubiquitinase POH1-mediated regulation of the Hippo/YAP signaling pathway in pancreatic cancer not only suppresses pancreatic cancer progression and the activation of the Hippo/YAP axis both in vitro and in vivo but also inhibits tumorigenesis. Biochemical studies indicated that regulation of the Hippo/YAP signaling pathway in pancreatic cancer by the deubiquitinase POH1 inhibits K48-linked poly-ubiquitination of YAP, thereby enhancing the transcriptional activity of the Hippo/YAP axis. ChIP assays demonstrated that YAP directly enhances POH1 gene transcription by binding to its promoter region, indicating that POH1 functions as both an upstream regulator and a downstream target of the Hippo pathway in pancreatic cancer. The study indicates that POH1 and the Hippo pathway significantly contribute to pancreatic cancer progression, highlighting POH1-targeting drugs as promising therapeutic options.