ZFP64 Promotes Gallbladder Cancer Progression through Recruiting HDAC1 to Activate NOTCH1 Signaling Pathway

SIMPLE SUMMARY: Gallbladder cancer (GBC) is one of the solid tumors with the worst prognosis, and existing treatments for GBC are not effective. Understanding the disease process of GBC from the perspective of molecular mechanisms is helpful in developing new therapies. In this study, we aimed at exploring a meaningful regulator in GBC. Through a series of in vitro and in vivo assays, we confirmed that zinc finger protein 64 (ZFP64) is a potential promoter and ZFP64-Notch1-HDAC1 is an essential oncogenic axis in GBC progression. Targeting ZFP64 may pave the way for the development of effective therapy for this disease. ABSTRACT: The lack of meaningful and effective early-stage markers remains the major challenge in the diagnosis of gallbladder cancer (GBC) and a huge barrier to timely treatment. Zinc finger protein 64 (ZFP64), a member of the zinc finger protein family, is considered to be a promising predictor in multiple tumors, but its potential effect in GBC still remains unclear. Here, we identified that ZFP64 was a vital regulatory protein in GBC. We found that ZFP64 expressed higher in GBC gallbladder carcinoma tissues than in normal tissues and was positively correlated with poor prognosis. Furthermore, ZFP64 was responsible for the migration, invasion, proliferation, anti-apoptosis, and epithelial mesenchymal transition (EMT) of GBC cells in vitro and in vivo. Mechanistically, through Co-IP assay, we confirmed that ZFP64 recruits HDAC1 localized to the promoter region of NUMB for deacetylation and therefore inhibits NUMB expression. The downregulation of NUMB enhanced the activation of the Notch1 signaling pathway, which is indispensable for the GBC-promotion effect of ZFP64 on GBC. In conclusion, ZFP64 regulated GBC progression and metastasis through upregulating the Notch1 signaling pathway, and thus ZFP64 is expected to become a new focus for a GBC prognostic marker and targeted therapy.