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Science 335 (6066): 348-353

Copyright © 2012 by the American Association for the Advancement of Science

A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis

Jessica D. Kessler,1,2 Kristopher T. Kahle,3,4 Tingting Sun,1 Kristen L. Meerbrey,1,2 Michael R. Schlabach,3 Earlene M. Schmitt,1,2 Samuel O. Skinner,1,5 Qikai Xu,3 Mamie Z. Li,3 Zachary C. Hartman,6 Mitchell Rao,2 Peng Yu,2 Rocio Dominguez-Vidana,1,2 Anthony C. Liang,3 Nicole L. Solimini,3 Ronald J. Bernardi,7 Bing Yu,8 Tiffany Hsu,1,2 Ido Golding,1,5 Ji Luo,8 C. Kent Osborne,9,10,11,12 Chad J. Creighton,9,13 Susan G. Hilsenbeck,9,10,13 Rachel Schiff,9,10,11,12 Chad A. Shaw,2 Stephen J. Elledge,3,* Thomas F. Westbrook1,2,7,9,*

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.

1 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3 Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA.
4 Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02115, USA.
5 Department of Physics, University of Illinois, Urbana, IL 61801, USA.
6 Department of Clinical Cancer Prevention, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
7 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
8 Medical Oncology Branch, National Cancer Institute, Center Drive, Bethesda, MD 20892, USA.
9 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
10 The Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
11 Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
12 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
13 Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA.

* To whom correspondence should be addressed. E-mail: thomasw{at}bcm.edu (T.F.W.); selledge{at}genetics.med.harvard.edu (S.J.E.)

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