Identification of a recurrent transforming UBR5-ZNF423 fusion gene in EBV-associated nasopharyngeal carcinoma
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AbstractNasopharyngeal 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. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
All Author(s) ListChung G.T.Y., Lung R.W.M., Hui A.B.Y., Yip K.Y.L., Woo J.K.S., Chow C., Tong C.Y.K., Lee S.-D., Yuen J.W.F., Lun S.W.M., Tso K.K.Y., Wong N., Tsao S.-W., Yip T.T.C., Busson P., Kim H., Seo J.-S., O'Sullivan B., Liu F.-F., To K.-F., Lo K.-W.
Journal nameJournal of Pathology
Year2013
Month10
Day1
Volume Number231
Issue Number2
PublisherJohn Wiley & Sons Inc.
Place of PublicationUnited States
Pages158 - 167
ISSN0022-3417
eISSN1096-9896
LanguagesEnglish-United Kingdom
KeywordsEpstein-Barr virus, gene rearrangement, nasopharyngeal carcinoma, oncogene, transcriptome sequencing, UBR5-ZNF423 fusion

Last updated on 2020-19-09 at 03:29