SUMO-specific protease 2-mediated deSUMOylation is required for NDRG2 stabilization in gastric cancer cells.

N-myc downstream regulated gene 2 (NDRG2) is frequently down-regulated in various cancers and functions as a candidate tumor suppressor gene. NDRG2 has been shown to be SUMOylated on the lysine 333 residue, which promoted its ubiquitination and sequentially degradation by the SUMO-targeted ubiquitin E3 ligase RNF4. However, how to regulated NDRG2 deSUMOylation process remains largely unknown. Here, we report that Sentrin/SUMO specific protease (SENP2) was down-regulated in clinic gastric cancer samples and possessed a tumor-suppressive role in gastric cancer. At the molecular level, we found that SENP2 interacts with NDRG2 and mediates the de-SUMOylation process of NDRG2. Overexpression of SENP2 stabilized NDRG2, whereas silencing SENP2 caused rapid NDRG2 SUMOylation and degradation, indicating SENP2 antagonizes NDRG2 ubiquitination and degradation, thereby promoting the stability and function of this protein. Thus, our study reveals that SENP2 acts as a tumor suppressor which is deregulated in gastric cancer and the specific de-SUMOylation activity of SENP2 for NDRG2 is critical for it stabilization as well as gastric cancer cells proliferation.