title: A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis.
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.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Kessler
authors.forename: Kristopher T
authors.initials: KT
authors.lastname: Kahle
authors.forename: Tingting
authors.initials: T
authors.lastname: Sun
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Meerbrey
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schlabach
authors.forename: Earlene M
authors.initials: EM
authors.lastname: Schmitt
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Skinner
authors.forename: Qikai
authors.initials: Q
authors.lastname: Xu
authors.forename: Mamie Z
authors.initials: MZ
authors.lastname: Li
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Mitchell
authors.initials: M
authors.lastname: Rao
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Rocio
authors.initials: R
authors.lastname: Dominguez-Vidana
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Liang
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Solimini
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Bernardi
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hsu
authors.forename: Ido
authors.initials: I
authors.lastname: Golding
authors.forename: Ji
authors.initials: J
authors.lastname: Luo
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D008941:Spindle Apparatus / Q000502:physiology; D058207:Sumoylation; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C470301:UBA2 protein, human; C470299:SAE1 protein, human; D044764:Ubiquitin-Activating Enzymes