A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis
2012
Kessler, Jessica D. | Kahle, Kristopher T. | Sun, Tingting | Meerbrey, Kristen L. | Schlabach, Michael R. | Schmitt, Earlene M. | Skinner, Samuel O. | Xu, Qikai | Li, Mamie Z. | Hartman, Zachary C. | Rao, Mitchell | Yu, Peng | Dominguez-Vidana, Rocio | Liang, Anthony C. | Solimini, Nicole L. | Bernardi, Ronald J. | Yu, Bing | Hsu, Tiffany | Golding, Ido | Luo, Ji | Osborne, C Kent | Creighton, Chad J. | Hilsenbeck, Susan G. | Schiff, Rachel | Shaw, Chad A. | Elledge, Stephen J. | Westbrook, Thomas F.
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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