Publication Date:
2011-12-14
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059214/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059214/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kessler, Jessica D -- Kahle, Kristopher T -- Sun, Tingting -- Meerbrey, Kristen L -- Schlabach, Michael R -- Schmitt, Earlene M -- Skinner, Samuel O -- Xu, Qikai -- Li, Mamie Z -- Hartman, Zachary C -- Rao, Mitchell -- Yu, Peng -- Dominguez-Vidana, Rocio -- Liang, Anthony C -- Solimini, Nicole L -- Bernardi, Ronald J -- Yu, Bing -- Hsu, Tiffany -- Golding, Ido -- Luo, Ji -- Osborne, C Kent -- Creighton, Chad J -- Hilsenbeck, Susan G -- Schiff, Rachel -- Shaw, Chad A -- Elledge, Stephen J -- Westbrook, Thomas F -- CA149196/CA/NCI NIH HHS/ -- P30 CA125123/CA/NCI NIH HHS/ -- P50 CA058183/CA/NCI NIH HHS/ -- R01 GM082837/GM/NIGMS NIH HHS/ -- R01GM082837/GM/NIGMS NIH HHS/ -- T32CA090221-09/CA/NCI NIH HHS/ -- T32HD05520/HD/NICHD NIH HHS/ -- U54 CA149196/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Jan 20;335(6066):348-53. doi: 10.1126/science.1212728. Epub 2011 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22157079" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Breast Neoplasms/*genetics/metabolism/mortality/pathology
;
Cell Cycle
;
Cell Line, Tumor
;
*Cell Transformation, Neoplastic
;
Female
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic
;
*Genes, myc
;
Humans
;
Mammary Neoplasms, Experimental/genetics/metabolism/mortality/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/*genetics/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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