The Effect of Neddylation Blockade on Slug-Dependent Cancer Cell Migration Is Regulated by p53 Mutation Status

Abstract

Simple Summary Neddylation is a process in which the small ubiquitin-like molecule NEDD8 is covalently conjugated to target proteins by sequential enzymatic reactions. Because neddylation plays critical roles in regulating cancer growth and migration, it is emerging as an effective therapeutic target. The major tumor suppressor protein p53 reduces cancer cell migration and is inhibited by neddylation. As p53 is lost or mutated in 50% of various cancer types, this study attempted to investigate how neddylation affects cancer cell migration according to p53 status. Neddylation blockade reduced or caused no change in migration of wild type or mutant p53 cancer cell lines. In contrast, neddylation blockade induced migration of p53-null cancer cell lines. These results were mediated by the differential effect of neddylation blockade on the epithelial-mesenchymal transition activator Slug according to p53 status. Thus, the p53 status of cancer cells should be considered when developing neddylation-targeted anticancer drugs. The tumor suppressor protein p53 is frequently inactivated in human malignancies, in which it is associated with cancer aggressiveness and metastasis. Because p53 is heavily involved in epithelial-mesenchymal transition (EMT), a primary step in cell migration, p53 regulation is important for preventing cancer metastasis. p53 function can be modulated by diverse post-translational modifications including neddylation, a reversible process that conjugates NEDD8 to target proteins and inhibits the transcriptional activity of p53. However, the role of p53 in cancer migration by neddylation has not been fully elucidated. In this study, we reported that neddylation blockade induces cell migration depending on p53 status, specifically via the EMT-promoting transcription factor Slug. In cancer cell lines expressing wild type p53, neddylation blockade increased the transcriptional activity of p53 and expression of its downstream genes p21 and MDM2, eventually promoting proteasomal degradation of Slug. In the absence of p53, neddylation blockade increased cell migration by activating the PI3K/Akt/mTOR/Slug signaling axis. Because mutant p53 was transcriptionally inactivated but maintained the ability to bind to Slug, neddylation blockade did not affect the migration of cells expressing mutant p53. Our findings highlight how the p53 expression status influences neddylation-mediated cell migration in multiple cancer cell lines via Slug.