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In Vitro SUMOylation Assay to Study SUMO E3 Ligase Activity
Published on: January 29, 2018
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
Summary
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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