Abstract
N-Myc downstream-regulated gene 2 (NDRG2) protein is a tumor suppressor that inhibits cancer growth, metastasis and invasion. The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin through its selective recognition and ubiquitination of SUMO-modified proteins. We evaluated NDRG2 SUMOylation in lung adenocarcinoma cells and its underlying molecular mechanism. The results showed that NDRG2 is covalently modified by SUMO1 at K333, which suppressed anchorage independent adenocarcinoma cell proliferation and tumor growth. In human lung adenocarcinomas cells, RNF4 targeted NDRG2 to proteasomal degradation by stimulating its SUMOylation. Endogenous RNF4 expression was increased in human lung adenocarcinomas cells, and there was a concomitant upregulation of SUMO. These findings indicate that SUMOylation of NDRG2 is necessary for its tumor suppressor function in lung adenocarcinoma and that RNF4 increases the efficiency of this process.
Highlights
Lung cancer was the most commonly diagnosed cancer and the leading cause of cancer death among males worldwide in 2008
We present evidence that N-myc downstream-regulated gene 2 (NDRG2) is modified by SUMOylation catalyzed by RING finger protein 4 (RNF4) and that SUMOylation is required for NDRG2 regulated tumorigenesis in lung carcinoma cells
The expression of NDRG2 was www.impactjournals.com/oncotarget comparable in all clones when assessed by western blotting, indicating that the two mutations did not affect the NDRG2 transcription rate and protein stability
Summary
Lung cancer was the most commonly diagnosed cancer and the leading cause of cancer death among males worldwide in 2008. The best approach for the treatment of lung cancer is currently complete surgical removal of the tumor and adjacent lymph nodes. There is an urgent need to explore new targets and therapeutic approaches to the treatment of lung cancer. N-myc downstream-regulated gene 2 (NDRG2) is a 41-kDa cytoplasmic protein of NDRG family. It is involved in multiple biological processes, including cell growth, differentiation, and apoptosis [3]. Evidence suggests that NDRG2 may act as a tumor suppressor in various cancers. The actions of NDRG2 in lung cancer remain unclear,
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