FBXW2 Inhibits Prostate Cancer Progression and Metastasis Via Promoting EGFR Ubiquitylation and Degradation

Background: The process of ubiquitylation, carried out by a three-step enzymatic cascade, maintains the balance of intracellular proteins and the stability of their functions. FBXW2 is a novel F-box protein, and acts as a tumor suppressor gene in lung cancer by directly degrading substrates or regulating the other E3 ligases. However, whether or how FBXW2 regulates prostate cancer (PCa) tumorigenesis and progression is still unclear.Methods: The expression levels of FBXW2 in PCa tissues and matched non-tumor tissues were detected by immunoblotting and qPCR. Cell counting kit-8, wound-healing assay, invasion assay, apoptosis and cell cycle assays, and animal experiments were performed to identify the function of FBXW2 in PCa cells. Half-life analysis, immunoprecipitation, and the in vivo ubiquitylation assay were performed to determine how FBXW2 regulates EGFR and its downstream signaling pathway.Results: FBXW2 expression was lowly expressed in highly-progressive PCa tissues and PCa cell lines. Augmented FBXW2 expression suppressed PCa cell progression and metastasis by repressing EGFR downstream proteins, while FBXW2 depletion had opposite effects. Overexpression of FBXW2 inhibited tumor growth, and even osteolytic bone destruction. Furthermore, FBXW2 and EGFR protein levels were inversely correlated in PCa cell lines and patient tumor tissues. EGFR protein level and its half-life was extended by FBXW2 depletion. While the basal level of EGFR was decreased, and its half-life was shortened upon overexpression of FBXW2-WT but not its dominant negative mutant. Intriguingly, FBXW2 promoted EGFR ubiquitylation and degradation via its binding motif (TSNNST) on EGFR, thereby elevated FBXW2 abrogated the PCa cell growth and metastasis caused by EGF stimulation.Conclusions: Collectively, our data shows that FBXW2 inhibits PCa cell progression and metastasis by promoting EGFR ubiquitylation and degradation, and would be a novel tumor suppressor for PCa.