期刊
SCIENCE
卷 335, 期 6066, 页码 348-353出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1212728
关键词
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资金
- NIH [T32HD05520/T32CA090221-09, R01GM082837, CA149196]
- U.S. Department of Defense [W81XWH-10-1-0354]
- Human Frontier Science Program [RGY70/2008]
- Welch Foundation [Q-1759]
- NSF [082265]
- Susan G. Komen for the Cure [KG090355]
- CPRIT [RP120583]
- Specialized Program of Research Excellence developmental grant [P50 CA058183]
- SU2C-American Association for Cancer Research
- U.S. Army [W81XWH0410197]
- U.S. Department of Defense (DOD) [W81XWH0410197] Funding Source: U.S. Department of Defense (DOD)
Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we used a genome-wide RNA interference screen to search for Myc-synthetic lethal genes and uncovered a role for the SUMO-activating enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Inactivation of SAE2 leads to mitotic catastrophe and cell death upon Myc hyperactivation. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc switchers (SMS genes) is required for mitotic spindle function and to support the Myc oncogenic program. SAE2 is required for growth of Myc-dependent tumors in mice, and gene expression analyses of Myc-high human breast cancers suggest that low SAE1 and SAE2 abundance in the tumors correlates with longer metastasis-free survival of the patients. Thus, inhibition of SUMOylation may merit investigation as a possible therapy for Myc-driven human cancers.
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