title: Identification of a recurrent transforming UBR5-ZNF423 fusion gene in EBV-associated nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer which is prevalent in southern China, south-east Asia and northern Africa. The development and stepwise progression of NPC involves accumulation of multiple gross genetic changes during the clonal expansion of Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cell population. Here, using paired-end whole-transcriptome sequencing, we discovered a number of chimeric fusion transcripts in a panel of EBV-positive tumour lines. Among these transcripts, a novel fusion of ubiquitin protein ligase E3 component n-recognin 5 (UBR5) on 8q22.3 and zinc finger protein 423 (ZNF423) on 16q12.1, identified from the NPC cell line C666-1, was recurrently detected in 12/144 (8.3%) of primary tumours. The fusion gene contains exon 1 of UBR5 and exons 7-9 of ZNF423 and produces a 94 amino acid chimeric protein including the original C-terminal EBF binding domain (ZF29-30) of ZNF423. Notably, the growth of NPC cells with UBR5-ZNF423 rearrangement is dependent on expression of this fusion protein. Knock-down of UBR5-ZNF423 by fusion-specific siRNA significantly inhibited the cell proliferation and colony-forming ability of C666-1 cells. The transforming ability of UBR5-ZNF423 fusion was also confirmed in NIH3T3 fibroblasts. Constitutive expression of UBR5-ZNF423 in NIH3T3 fibroblasts significantly enhanced its anchorage-independent growth in soft agar and induced tumour formation in a nude mouse model. These findings suggest that expression of UBR5-ZNF423 protein might contribute to the transformation of a subset of NPCs, possibly by altering the activity of EBFs (early B cell factors). Identification of the oncogenic UBR5-ZNF423 provides new potential opportunities for therapeutic intervention in NPC.
authors.affiliation: Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, SAR; Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, SAR.
authors.forename: Grace Ty
authors.initials: GT
authors.lastname: Chung
authors.forename: Raymond Wm
authors.initials: RW
authors.lastname: Lung
authors.forename: Angela By
authors.initials: AB
authors.lastname: Hui
authors.forename: Kevin Yl
authors.initials: KY
authors.lastname: Yip
authors.forename: John Ks
authors.initials: JK
authors.lastname: Woo
authors.forename: Chit
authors.initials: C
authors.lastname: Chow
authors.forename: Carol Yk
authors.initials: CY
authors.lastname: Tong
authors.forename: Sau-Dan
authors.initials: SD
authors.lastname: Lee
authors.forename: Jessie Wf
authors.initials: JW
authors.lastname: Yuen
authors.forename: Samantha Wm
authors.initials: SW
authors.lastname: Lun
authors.forename: Ken Ky
authors.initials: KK
authors.lastname: Tso
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Timothy Tc
authors.initials: TT
authors.lastname: Yip
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
authors.forename: Hyungtae
authors.initials: H
authors.lastname: Kim
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
authors.forename: Ka-Fai
authors.initials: KF
authors.lastname: To
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000821:virology; D009857:Oncogenes / Q000235:genetics; D011506:Proteins; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D014162:Transfection; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C031017:ornithine decarboxylase antizyme; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Epstein-Barr virus; UBR5-ZNF423 fusion; gene rearrangement; nasopharyngeal carcinoma; oncogene; transcriptome sequencing