FAT4-USP51 complex regulates the proliferation and invasion of endometrial cancer via Hippo pathway

Recent studies have identified FAT tumour suppressor homologue 4 (FAT4), an essential component of adherents junctions, involved in several cancers. However, its role in endometrial cancer (EC) remains unclear. In this study, we first analyzed the association between FAT4 expression and tumour stage, tumour type, and patient prognosis in 552 tumour samples and 35 non-tumour samples from The Cancer Genome Atlas (TCGA) database. The association of decreased FAT4 expression with advanced signature (lymph node metastasis, lymphovascular invasion and muscular infiltration) in EC patients was also confirmed by our own dataset. Stable FAT4 Knockdown promoted EC cell lines proliferation and invasion. FAT4 overexpression inhibited the parental cell phenotype. FAT4 silencing resulted in decreased phosphorylation of the LATS1/2 and YAP while increased YAP nuclear translocation which was associated with the promotion of proliferation and invasion. PCR array analysis of the negative control and shFAT4 HEC-1B cell lines revealed that the deubiquitinating enzyme USP51 was a FAT4 interacting target gene. Ablating USP51 by shRNA decreased cellular FAT4 protein level while overexpression of USP51 increased FAT4 protein level. Coimmunoprecipitation confirmed the direct binding of FAT4 and USP51 which was essential for FAT4's function in EC. The growth inhibitory effect of FAT4 was also attenuated by USP51 down-regulation. In conclusion, suppression of FAT4 by inactivation of deubiquitinating enzyme USP51 promoted proliferation and invasion of EC cells via inhibiting Hippo pathway.