The oncogene metadherin interacts with the known splicing proteins YTHDC1, Sam68 and T-STAR and Plays a novel role in alternative mRNA splicing

Hayley J. Luxton, Benjamin S. Simpson, Ian G. Mills, Nicola R. Brindle, Zeba Ahmed, Vasilis Stavrinides, Susan Heavey, Stefan Stamm, Hayley C. Whitaker

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Oncogenic metadherin is a key contributor to tumourigenesis with metadherin expression and cytoplasmic localisation previously linked to poor survival. A number of reports have shown metadherin localises specifically to nuclear speckles known to be rich in RNA-binding proteins including the splicing proteins YTHDC1, Sam68 and T-STAR, that have been shown to select alternative splice sites in mRNA of tumour-associated proteins including BRCA, MDM2 and VEGF. Here we investigate the interaction and relationship between metadherin and the splice factors YTHDC1, T-STAR and Sam68. Using a yeast two-hybrid assay and immunoprecipitation we show that metadherin interacts with YTHDC1, Sam68 and T-STAR and demonstrate that T-STAR is significantly overexpressed in prostate cancer tissue compared to benign prostate tissue. We also demonstrate that metadherin influences splice site selection in a dose-dependent manner in CD44v5-luc minigene reporter assays. Finally, we demonstrate that prostate cancer patients with higher metadherin expression have greater expression of the CD44v5 exon. CD44v5 expression could be used to discriminate patients with poor outcomes following radical prostatectomy. In this work we show for the first time that metadherin interacts with, and modulates, the function of key components of splicing associated with cancer development and progression.

Original languageEnglish
Article number1233
JournalCancers
Volume11
Issue number9
DOIs
StatePublished - Sep 2019

Bibliographical note

Funding Information:
We are grateful to The Urology Foundation for funding HL and Rosetrees Trust for funding BS, The Medical Research Council for funding VS. Additionally we are grateful to Prostate Cancer UK and Movember for their support via the Prostate Cancer Centre of Excellence and TLD-PF16-004 grant that funds SH and supports the work in our laboratory.

Funding Information:
Funding: We are grateful to The Urology Foundation for funding HL and Rosetrees Trust for funding BS, The Medical Research Council for funding VS. Additionally we are grateful to Prostate Cancer UK and Movember for their support via the Prostate Cancer Centre of Excellence and TLD-PF16-004 grant that funds SH and supports the work in our laboratory.

Publisher Copyright:
© 2019 by the authors.

Keywords

  • Alternative splicing
  • CD44
  • Prostate cancer
  • SAM68
  • YTHDC1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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