Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Gastrointestinal Endoscope Center, Cancer Hospital of Guizhou Medical University, Guiyang 550001, Guizhou, China.
Cancer Biomark. 2017 Dec 12;21(1):195-201. doi: 10.3233/CBM-170651.
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.
N- myc 下游调节基因 2（NDRG2）在各种癌症中经常下调，作为候选肿瘤抑制基因发挥作用。已证实 NDRG2 在赖氨酸 333 残基上发生 SUMO 化，促进其泛素化，并通过 SUMO 靶向泛素 E3 连接酶 RNF4 进行顺序降解。然而，NDRG2 的去 SUMO 化过程如何调节仍知之甚少。在这里，我们报告 Sentrin/SUMO 特异性蛋白酶（SENP2）在临床胃癌样本中下调，并在胃癌中具有肿瘤抑制作用。在分子水平上，我们发现 SENP2 与 NDRG2 相互作用，并介导 NDRG2 的去 SUMO 化过程。SENP2 的过表达稳定了 NDRG2，而沉默 SENP2 导致 NDRG2 的 SUMO 化和快速降解，表明 SENP2 拮抗 NDRG2 的泛素化和降解，从而促进该蛋白的稳定性和功能。因此，我们的研究表明，SENP2 作为一种肿瘤抑制因子在胃癌中失调，SENP2 对 NDRG2 的特异性去 SUMO 化活性对其稳定以及胃癌细胞的增殖至关重要。
