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The Evolutionarily Conserved Cassette Exon 7b Drives ERG's Oncogenic Properties

Jumbe, Samantha; Porazinski, Sean; Oltean, Sebastian; Mansell, Jason; Vahabi, Bahareh; Wilson, Ian; Ladomery, Michael

Authors

Samantha Jumbe Samantha.Jumbe@uwe.ac.uk

Sean Porazinski Sean.Porazinski@uwe.ac.uk

Sebastian Oltean

Jason Mansell Jason.Mansell@uwe.ac.uk
Associate Professor in Biomedical Sciences



Abstract

© 2018 The oncogene ERG encodes an ETS family transcription factor and is implicated in blood, vascular, and bone development and in prostate, blood, and bone cancer. The ERG gene is alternatively spliced; of particular interest is its cassette exon 7b which adds 24 amino acids, in frame, to the transcriptional activation domain. Higher exon 7b inclusion rates are associated with increased cell proliferation and advanced prostate cancer. The 24 amino acids encoded by exon 7b show evolutionary conservation from humans to echinoderms, highlighting their functional importance. Throughout evolution, these 24 amino acids are encoded by a distinct short exon. Splice-switching oligonucleotides based on morpholino chemistry were designed to induce skipping of ERG exon 7b in MG63 osteosarcoma and VCaP prostate cancer cells. Induction of exon 7b skipping reduced cell proliferation and invasion, increased apoptosis in vitro, and reduced xenograft growth in vivo. We also show that ERG's exon 7b is required for the induction of tissue nonspecific alkaline phosphatase. Together, these findings show that the evolutionarily conserved cassette exon 7b is central to ERG's oncogenic properties.

Journal Article Type Article
Publication Date Jan 1, 2019
Journal Translational Oncology
Electronic ISSN 1936-5233
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 12
Issue 1
Pages 134-142
APA6 Citation Jumbe, S., Porazinski, S., Oltean, S., Mansell, J., Vahabi, B., Wilson, I., & Ladomery, M. (2019). The Evolutionarily Conserved Cassette Exon 7b Drives ERG's Oncogenic Properties. Translational Oncology, 12(1), 134-142. https://doi.org/10.1016/j.tranon.2018.09.001
DOI https://doi.org/10.1016/j.tranon.2018.09.001
Keywords ERG transcription factor, ERG cassette exon 7b, splice-switching oligonucleotides, morpholinos, TNSALP, osteoblast-like MG63 cells, osteosarcoma, VCaP prostate cancer cells
Publisher URL https://doi.org/10.1016/j.tranon.2018.09.001

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