Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor
| Autor: | Sai M Pulukuri, James Minissale, Neil F. Bence, Matt Duffey, Hirotake Mizutani, He Xu, Hu Zhigen, Lawrence R. Dick, Xingyue He, Dylan England, Erik Koenig, Pooja Shah, Xiaofeng Yang, Hua Liao, Teresa A. Soucy, James E. Brownell, Melissa Gallery, Claudia Rabino, John Newcomb, Hugues Bernard, John Bradley, Jianping Guo, Mike Sintchak, Zhong-Hua Yan, Kristina Xega, Steve Langston, Ryan Chau, Jessica Riceberg, Eric S. Lightcap |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Mutant SUMO protein Genes myc Mitosis Biology 03 medical and health sciences Small Ubiquitin-Related Modifier Proteins Chromosome Segregation Neoplasms parasitic diseases Tumor Cells Cultured Humans Enzyme Inhibitors Molecular Biology Cell Proliferation Regulation of gene expression Oncogene Cell growth Sumoylation Cell Biology Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology Cancer cell Protein Processing Post-Translational DNA Damage |
| Zdroj: | Nature chemical biology. 13(11) |
| ISSN: | 1552-4469 |
| Popis: | Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic-subunit (UBA2) S95N M97T mutant rescued SUMOylation loss and the mitotic defect induced by ML-792, thus confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins, thereby facilitating novel insights into SUMO biology. |
| Databáze: | OpenAIRE |
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