A SUMOylation-dependent Transcriptional Subprogram is Required for Myc-driven Tumorigenesis

Overview

Journal Science

Specialty Science

Date 2011 Dec 14

PMID 22157079

Citations 261

Authors

Jessica D Kessler

Kristopher T Kahle

Tingting Sun

Kristen L Meerbrey

Michael R Schlabach

Earlene M Schmitt

Samuel O Skinner

Qikai Xu

Mamie Z Li

Zachary C Hartman

Mitchell Rao

Peng Yu

Rocio Dominguez-Vidana

Anthony C Liang

Nicole L Solimini

Ronald J Bernardi

Bing Yu

Tiffany Hsu

Ido Golding

Ji Luo

C Kent Osborne

Chad J Creighton

Susan G Hilsenbeck

Rachel Schiff

Chad A Shaw

Stephen J Elledge

Thomas F Westbrook

Affiliations

Soon will be listed here.

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.

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