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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Kessler, JD; Kahle, KT; Sun, T; Meerbrey, KL; Schlabach, MR; Schmitt, EM; Skinner, SO; Xu, Q; Li, MZ; Hartman, ZC; Rao, M; Yu, P; Dominguez-Vidana, R; Liang, AC; Solimini, NL; Bernardi, RJ; Yu, B; Hsu, T; Golding, I; Luo, J; Osborne, CK; Creighton, CJ; Hilsenbeck, SG; Schiff, R; Shaw, CA; Elledge, SJ; Westbrook, TF

Published Date

  • January 20, 2012

Published In

Volume / Issue

  • 335 / 6066

Start / End Page

  • 348 - 353

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1212728

Citation Source

  • Scopus