Mapping the STK4/Hippo Signaling Network in Prostate Cancer Cells. Homo sapiens

The STK4-encoded MST1 serine-threonine kinase is the key component of the Hippo-YAP pathway. Dysregulation or loss of STK4 functions is linked to cancer with poor prognosis, but the mechanism remains elusive. Here, we investigated the effects of cytoplasm-, lipid raft-, and nuclear-localized STK4 on cell growth and gene expression in castration-resistant PC cells to better understand the mechanism of how STK4 signaling restricts the aggressive cancer cell phenotype. We demonstrated that lipid raft- and nuclear-localized STK4 cells showed superior growth suppressive effects ex vivo and in vivo compared with cytoplasm-localized STK4 cells. Using RNA sequencing and bioinformatics analysis, we identified several differentially expressed (DE) genes responding to STK4 expression in all three cell locations with respect to a vector control. The number of DE genes in lipid raft-, and nuclear-localized STK4 cells were much greater than DE genes in cytoplasm-localized STK4 cells. Functional annotation clustering of DE genes showed that as opposed to the cytoplasmic STK4 cells, the DE genes identified from lipid raft and nuclear STK4 cells were clustered for common cancer-associated pathways such as AR, PI3K-AKT, BMP/SMAD, GPCR, WNT, and RAS, but with a distinction of the JAK/STAT pathway that emerged only in nuclear STK4 cells. Overall, our findings suggest that the STK4/Hippo pathway restricts aggressive tumor cell phenotype by modulating an array of molecular pathways.