YAP induces FAK phosphorylation to inhibit gastric cancer cell proliferation via upregulation of HMGB1

Abstract

Yes associated protein (YAP) is the main effector protein in the Hippo pathway, regulating cell growth by binding to transcription factors in the nucleus. However, the mechanisms by which YAP regulates the development and progression of gastric cancer (GC) remain largely unknown. In this study, bioinformatics analysis determined that YAP was significantly upregulated in GC and associated with poor prognosis. In addition, YAP deletion inhibits proliferation and migration of GC cells in vitro, while overexpression of YAP has the opposite effect. Mechanistically, overexpression of YAP induced FAK phosphorylation in gastric cancer cells, whereas knockdown of YAP had the opposite effect. Importantly, translocation expressed mutant plasmid YAP-S94A (YAP1 mutant without TEAD binding site) did not significantly change the level of FAK phosphorylation. Furthermore, Verteporfin (a small molecule inhibitor of YAP) interrupted the YAP-TEAD interaction and inhibited FAK phosphorylation, confirming that YAP can induce FAK phosphorylation in a TEAD-dependent manner. In addition, the silencing of FAK or the use of FAK inhibitors inhibited the aggregation of YAP proteins in the nucleus, forming a FAK-YAP positive feedback loop. Finally, we identify the FAK upstream gene, HMGB1, as a direct transcriptional target of YAP-TEAD. Silencing HMGB1 reversed YAP-induced FAK activation as well as cell proliferation and migration. Collectively, our results reveal a new signalling axis, YAP/HMGB1/FAK, in the regulation of cell proliferation and migration, and provide new insights into the crosstalk between Hippo signalling and cell proliferation.