FAM189A2 activates Hippo signaling pathway by abrogating WWP2-mediated LATS1 ubiquitination, to inhibit the glycolysis and proliferation processes of lung adenocarcinoma.

BACKGROUND: Metabolic abnormalities have become a prominent hallmark of malignant tumor and play a crucial role in the occurrence and development of lung adenocarcinoma (LUAD). however, the underlying mechanism involved this process is still far from being fully elucidated. In this study, we aimed to explore the essential factors regulating the glycolysis and proliferation process in LUAD. METHODS: Bioinformation and immunohistochemistry were applied to screen and verify the expression pattern of the vital factors in LUAD. A series of biological function assays, including Cell Counting Kit 8 (CCK8), colony formation, 5-ethynyl-2'-deoxyuridine‌ (EdU), seahorse assays and nude mouse transplantation tumor assays, were performed to demonstrate the impact of the family with sequence similarity 189 member A2 (FAM189A2) on the glycolysis and proliferation process in LUAD. Co-immunoprecipitation, immunofluorescence and dual-luciferase reporter gene and RT-qPCR were used to verify the FAM129A2 and the WW domains of E3 ubiquitin ligase (WWP2) interaction, as well as the influence of their combination on large tumour suppressor-1 (LATS1) ubiquitination level and Hippo signaling pathway activity. RESULTS: FAM189A2 was weakly expressed in the cytoplasm of LUAD, and associated with the poor prognosis of patients. FAM189A2 overexpression inhibited the glycolysis and proliferation processes of LUAD cells in vitro. Meanwhile, both the processes were enhanced following FAM189A2 knockdown. Mechanistically, FAM189A2 was identified to interact with WWP2 through its own PPxY motifs, hence weakened the WWP2-LATS1 affinity and inhibited the WWP2-mediated LATS1 ubiquitination, which ultimately resulted in a reduced yes-associated protein (YAP) nuclear translocation. In addition, Verteporfin (Hippo pathway inhibitor) or YAP knockdown could eliminate the biological effects of promoting proliferation and glycolysis in LUAD cells caused by FAM189A1 silence. CONCLUSIONS: FAM189A2 can be considered as a potential diagnostic and prognostic marker associated with LUAD, and suppresses the proliferation and glycolytic metabolism of LUAD cells via WWP2-LATS1-YAP signaling, which will provide a corresponding theoretical foundation for the development of small molecule inhibitors.