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.
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ABSTRACT: The first joint meeting of the International Society for Cellular Oncology (ISCO) and the European Workshop on Cytogenetics and Molecular Genetics of Solid Tumors (EWCMST), organized by Bauke Ylstra, Juan Cigudosa and Nick Gilbert, was held from 4 to 8 March, 2012 in Palma de Mallorca, Spain. This meeting provided a novel and unique opportunity to jointly present the latest updates on the genetics of cancer and its implications for diagnosis, prognosis and therapy, now and in the future. Various aspects were highlighted, including the identification of effective therapeutic targets, the role of cellular senescence in tumor development and therapy, chromosome translocations in leukemias and solid tumors, mechanisms underlying fragile sites and chromosome instability, tumor-associated 'omics' landscapes, genetic and epidemiologic risk factors, the role of tissue and cancer stem cells, angiogenesis and the tumor micro-environment, and the epigenetics of cancer. In this report, new insights and clinical advancements related to these various topics are provided, based on information presented at the meeting.Cellular oncology (Dordrecht). 06/2012; 35(3):139-47.
Samuel O Skinner