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Overexpression of full-length ETV1 transcripts in clinical prostate cancer due to gene translocation.

Journal article
Authors Delila Gasi
Hetty A van der Korput
Hannie C Douben
Annelies de Klein
Corrina M de Ridder
Wytske M van Weerden
Jan Trapman
Published in PloS one
Volume 6
Issue 1
Pages e16332
ISSN 1932-6203
Publication year 2011
Published at Institute of Clinical Sciences
Pages e16332
Language en
Links dx.doi.org/10.1371/journal.pone.001...
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Chromosomes, Human, DNA-Binding Proteins, genetics, Gene Expression Regulation, Neoplastic, Humans, Male, Prostatic Neoplasms, genetics, Protein Isoforms, RNA, Neoplasm, analysis, Transcription Factors, genetics, Translocation, Genetic
Subject categories Biological Sciences, Clinical Medicine

Abstract

ETV1 is overexpressed in a subset of clinical prostate cancers as a fusion transcript with many different partners. However, ETV1 can also be overexpressed as a full-length transcript. Full-length ETV1 protein functions differently from truncated ETV1 produced by fusion genes. In this study we describe the genetic background of full-length ETV1 overexpression and the biological properties of different full-length ETV1 isoforms in prostate cancer. Break-apart FISH showed in five out of six patient samples with overexpression of full-length ETV1 a genomic rearrangement of the gene, indicating frequent translocation. We were able to study the rearrangements in more detail in two tumors. In the first tumor 5'-RACE on cDNA showed linkage of the complete ETV1 transcript to the first exon of a prostate-specific two exon ncRNA gene that maps on chromosome 14 (EST14). This resulted in the expression of both full-length ETV1 transcripts and EST14-ETV1 fusion transcripts. In chromosome spreads of a xenograft derived from the second prostate cancer we observed a complex ETV1 translocation involving a chromosome 7 fragment that harbors ETV1 and fragments of chromosomes 4 and 10. Further studies revealed the overexpression of several different full-length transcripts, giving rise to four protein isoforms with different N-terminal regions. Even the shortest isoform synthesized by full-length ETV1 stimulated in vitro anchorage-independent growth of PNT2C2 prostate cells. This contrasts the lack of activity of even shorter N-truncated ETV1 produced by fusion transcripts. Our findings that in clinical prostate cancer overexpression of full-length ETV1 is due to genomic rearrangements involving different chromosomes and the identification of a shortened biologically active ETV1 isoform are highly relevant for understanding the mechanism of ETV1 function in prostate cancer.

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