title: Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma.
abstract: Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2)-directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoellein
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, FL;
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schoeffmann
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: Steidle
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, FL;
authors.forename: Franz X
authors.initials: FX
authors.lastname: Schaub
authors.affiliation: Institute of Pathology and Clinical Cancer Center Mainfranken, Universität Würzburg, Würzburg, Germany;
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, Munich, Germany;
authors.forename: Iina
authors.initials: I
authors.lastname: Laitinen
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Lisa
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Department of Cell/Tissue Biology, University of California, San Francisco, San Francisco, CA; and.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Department of Surgery, Sahlgrenska Cancer Center, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Jonas A
authors.initials: JA
authors.lastname: Nilsson
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, FL;
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
mesh_terms: D048729:Anacardic Acids / Q000494:pharmacology; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011123:Polyploidy; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation / Q000187:drug effects; D014158:Transcription, Genetic; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: D048729:Anacardic Acids; D016271:Proto-Oncogene Proteins c-myc; C088115:anacardic acid; D044764:Ubiquitin-Activating Enzymes