Article

A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis.

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Science (impact factor: 31.2). 12/2011; 335(6066):348-53. DOI:10.1126/science.1212728 pp.348-53
Source: PubMed

ABSTRACT 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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Keywords

cell death
 
genome-wide RNA interference screen
 
Inactivation
 
low SAE1
 
metastasis-free survival
 
mitotic spindle function
 
Myc hyperactivation
 
Myc oncogenic program
 
Myc-dependent tumors
 
Myc-driven human cancers
 
Myc-high human breast cancers
 
Myc-synthetic lethal genes
 
oncogenic transcription factor
 
possible therapy
 
SAE1/2 enzymatic activity drives synthetic lethality
 
SAE2
 
SAE2 abundance
 
SMS genes
 
SUMOylation-dependent Myc switchers
 
transcriptional subprogram
 

Samuel O Skinner