E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated gene 4 motivates FOXA1 ubiquitination and restrains proliferation of diffuse large B-cell lymphoma cells via the Wnt/β-Catenin pathway.

Abstract

Neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) is an E3 ubiquitin ligase that recognizes substrates via protein-protein interactions and takes part in tumor development. This study aims to clarify NEDD4's functions in diffuse large B-cell lymphoma (DLBCL) and its downstream mechanisms. Collection of 53 DLBCL tissues and adjacent normal lymphoid tissues, and detection of NEDD4 and Forkhead box protein A1 (FOXA1) in the tissues were conducted. The selection of DLBCL cells was for FARAGE, and test of cells' advancement was after transfection. Analysis of NEDD4 and FOXA1's link, and test of Wnt/β-catenin pathway were implemented. In vivo tumor xenograft experiments were put into effect. Detection of the pathological conditions of tumor tissues and the positive Ki67 in the family was implemented. It came out NEDD4 was reduced in DLBCL tissues and cell lines, and FOXA1 was elevated; Enhancing NEDD4 or repressing FOXA1 refrained DLBCL cells' advancement; NEDD4 could combine with FOXA1 and trigger its ubiquitination and degradation; NEDD4 inactivates the Wnt/β-catenin pathway by motivating FOXA1 ubiquitination; NEDD4 enhancement refrained DLBCL growth in vivo. In conclusion, the E3 ubiquitin ligase NEDD4 accelerates FOXA1 ubiquitination but refrains DLBCL cell proliferation via the Wnt/β-Catenin pathway.