title: The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival.
abstract: Y-box binding protein 1 (YB-1) functions as a translational regulator and has been suggested to elevate MYC mRNA translation via an internal ribosome entry segment (IRES) point mutation in multiple myeloma (MM). We show that YB-1-mediated translation of MYC mRNA occurs independently of the reported IRES mutation, as 87 MM patients (n=88) and all tested human MM cell lines (HMCLs) were negative for the mutation. We show for the first time that positive MYC staining predicts YB-1 co-expression in malignant plasma cells and YB-1/MYC co-expression increases from 30% in medullary to 70% in extramedullary MM. YB-1 knockdown in HMCLs reduced both MYC protein levels and MYC mRNA in the polysomal fraction, providing a mechanism by which YB-1 controls MYC translation. MYC transcription of YB-1 is demonstrated in HMCLs as MYC knockdown resulted in reduced YB-1 protein and mRNA levels. Furthermore, MYC activation in non-malignant mouse embryonic fibroblasts (MEFs) increased YB-1 mRNA, clearly indicating that MYC drives YB-1 transcription. Importantly, perturbation of the MYC/YB-1 oncogenic circuit leads to apoptosis in HMCLs. Here, we demonstrate that these two proteins co-regulate each other via combined transcriptional/translational activity establishing their pivotal role in MM cell survival. We therefore suggest that targeting the YB-1/mRNA interaction provides a new strategy for MM drug development.
authors: Division of Haematology and Medical Oncology, Department of Internal Medicine II, Comprehensive Cancer Centre Mainfranken, University Hospital Würzburg, Würzburg, Germany. kurt.bommert@uni-wuerzburg.de
authors: K S
authors: KS
authors: Bommert
authors: M
authors: M
authors: Effenberger
authors: E
authors: E
authors: Leich
authors: M
authors: M
authors: Küspert
authors: D
authors: D
authors: Murphy
authors: C
authors: C
authors: Langer
authors: R
authors: R
authors: Moll
authors: S
authors: S
authors: Janz
authors: A
authors: A
authors: Mottok
authors: S
authors: S
authors: Weissbach
authors: A
authors: A
authors: Rosenwald
authors: R
authors: R
authors: Bargou
authors: K
authors: K
authors: Bommert
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation / Q000235:genetics; D011132:Polyribosomes; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051840:Y-Box-Binding Protein 1