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

Jessica D Kessler1, Kristopher T Kahle, Tingting Sun

  • 1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Science (New York, N.Y.)
|December 14, 2011
PubMed

Insights

Targeting the SUMO-activating enzyme (SAE1/2) causes synthetic lethality in Myc-driven cancers. Inhibiting SAE1/2 disrupts Myc

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Myc is a key oncogenic transcription factor often dysregulated in human cancers.
  • Identifying pathways that support the Myc oncogenic program is crucial for developing targeted therapies.

Purpose of the Study:

  • To identify genes that are synthetically lethal with Myc using a genome-wide RNA interference screen.
  • To investigate the role of the SUMO-activating enzyme (SAE1/2) in Myc-driven cancers.

Main Methods:

  • Genome-wide RNA interference screen to identify Myc-synthetic lethal genes.
  • Inactivation of SAE2 to observe effects on Myc hyperactivation.
  • Analysis of SUMOylation-dependent Myc switchers (SMS genes) and their role in mitotic spindle function.
  • Assessment of SAE2 requirement for Myc-dependent tumor growth in mice.
  • Gene expression analysis of Myc-high human breast cancers.

Main Results:

  • A role for the SUMO-activating enzyme (SAE1/2) was uncovered as a Myc-synthetic lethal gene.
  • Loss of SAE1/2 enzymatic activity leads to synthetic lethality with Myc.
  • Inactivation of SAE2 causes mitotic catastrophe and cell death upon Myc hyperactivation.
  • SAE2 inhibition switches Myc's transcriptional program from activation to repression.
  • A subset of SUMOylation-dependent Myc switchers (SMS genes) is essential for mitotic spindle function and the Myc oncogenic program.
  • SAE2 is required for the growth of Myc-dependent tumors in mice.
  • Low SAE1 and SAE2 abundance in human breast cancers correlates with longer metastasis-free survival.

Conclusions:

  • Inhibition of SUMOylation, specifically targeting SAE1/2, presents a potential therapeutic strategy for Myc-driven cancers.
  • Understanding the SUMOylation-dependent Myc switch mechanism offers insights into cancer biology.
  • Targeting SAE1/2 may be a promising avenue for treating Myc-dependent human malignancies.

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