Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells

Abstract

ABSTRACTFat4 functions as a Hippo signaling regulator which is involved in mammalian tissue development, differentiation and tumorigenesis. Loss of Fat4 due to frequent gene mutation was detected in a variety of tumors including gastric cancer, where Fat4 was recognized as a tumor suppressor, repressing cancer cell proliferation and adhesion. However, the detailed mechanisms linking Fat4 to its diverse functions and clinicopathological characteristics in gastric cancer remain unclear. Here, we silenced Fat4 using Fat4-shRNA in gastric cancer cells and found that this suppression led to the increase in phosphorylated Yap and nuclear accumulation of Yap, which associated to the promoted proliferation, migration and cell cycle progression. Then we transfected a full-length Fat4 into the Fat4-silenced cells, and found the decrease in phosphorylated Yap and inhibition of the cell cycle progression. Intriguingly, Fat4 reduction also leads to the accumulation of cytoplasmic β-catenin via the loss of restraining to cytoplasmic Yap instead of β-catenin transcription promotion. The Fat4-silenced cells which were treated with 5-FU, Cisplatin, Oxaliplatin and Paclitaxel individually demonstrated less sensitivities to these chemotherapy drugs compared with the control cells. Furthermore, immunohistochemical analysis revealed that Fat4 expression was significantly reduced in gastric cancer tissues compared with adjacent noncancerous tissues, and negatively correlated with tumor infiltration, lymph node metastasis and cumulative survival rate. In conclusion, Fat4 expression is deceased in gastric cancer cells, leading to nuclear translocation of Yap and correlates with poor prognosis.