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: 33.61). 12/2011; 335(6066):348-53. DOI: 10.1126/science.1212728
Source: PubMed


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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    • "RNAi technology enables a systematic interrogation of genes whose loss of function affects cell proliferation and viability (Ashworth and Bernards 2010; Kessler et al. 2012; Kumar et al. 2012). While a powerful method for identifying novel therapeutic targets, genome-wide RNAi screens can be laborious and expensive, requiring substantial infrastructure and specialized expertise for their execution. "
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