title: MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state.
abstract: The MYC oncogene regulates gene expression through multiple mechanisms, and its overexpression culminates in tumorigenesis. MYC inactivation reverses turmorigenesis through the loss of distinguishing features of cancer, including autonomous proliferation and survival. Here we report that MYC via miR-17-92 maintains a neoplastic state through the suppression of chromatin regulatory genes Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim. The enforced expression of miR-17-92 prevents MYC suppression from inducing proliferative arrest, senescence, and apoptosis and abrogates sustained tumor regression. Knockdown of the five miR-17-92 target genes blocks senescence and apoptosis while it modestly delays proliferative arrest, thus partially recapitulating miR-17-92 function. We conclude that MYC, via miR-17-92, maintains a neoplastic state by suppressing specific target genes.
authors.affiliation: Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Choi
authors.affiliation: Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Casey
authors.affiliation: Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Dill
authors.affiliation: Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA 94305, USA. Electronic address: dfelsher@stanford.edu.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D034622:RNA Interference; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
chemical_list: C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc