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

Science. 2012 Jan 20;335(6066):348-53. doi: 10.1126/science.1212728. Epub 2011 Dec 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, myc*
  • Humans
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / mortality
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Nude
  • Mitosis
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Spindle Apparatus / physiology
  • Sumoylation
  • Transcription, Genetic*
  • Transplantation, Heterologous
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors
  • Ubiquitin-Activating Enzymes / genetics*
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • UBA2 protein, human
  • SAE1 protein, human
  • Ubiquitin-Activating Enzymes

Associated data

  • GEO/GSE34055