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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)348-353
Number of pages6
JournalScience
Volume335
Issue number6066
DOIs
StatePublished - Jan 20 2012
Externally publishedYes

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    Kessler, J. D., Kahle, K. T., Sun, T., Meerbrey, K. L., Schlabach, M. R., Schmitt, E. M., Skinner, S. O., Xu, Q., Li, M. Z., Hartman, Z. C., Rao, M., Yu, P., Dominguez-Vidana, R., Liang, A. C., Solimini, N. L., Bernardi, R. J., Yu, B., Hsu, T., Golding, I., ... Westbrook, T. F. (2012). A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science, 335(6066), 348-353. https://doi.org/10.1126/science.1212728