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Media type:
E-Article
Title:
Insulin‐like growth factor 2 expression in prostate cancer is regulated by promoter‐specific methylation
Contributor:
Küffer, Stefan;
Gutting, Tobias;
Belharazem, Djeda;
Sauer, Christian;
Michel, Maurice S.;
Marx, Alexander;
Trojan, Lutz;
Ströbel, Philipp
imprint:
Wiley, 2018
Published in:Molecular Oncology
Language:
English
DOI:
10.1002/1878-0261.12164
ISSN:
1574-7891;
1878-0261
Origination:
Footnote:
Description:
<jats:p>Deregulation of the insulin‐like growth factor (<jats:styled-content style="fixed-case">IGF</jats:styled-content>) axis and dysbalance of components of the <jats:styled-content style="fixed-case">IGF</jats:styled-content> system as potential therapeutic targets have been described in different tumor types. <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 is a major embryonic growth factor and an important activator of <jats:styled-content style="fixed-case">IGF</jats:styled-content> signaling. It is regulated by imprinting in a development‐ and tissue‐dependent manner and has been implicated in a broad range of malignancies including prostate cancer (<jats:styled-content style="fixed-case">PC</jats:styled-content>a). Loss of imprinting (<jats:styled-content style="fixed-case">LOI</jats:styled-content>) usually results in bi‐allelic gene expression and increased levels of <jats:styled-content style="fixed-case">IGF</jats:styled-content>2. However, the regulatory mechanisms and the pathophysiological impact of altered <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 expression in <jats:styled-content style="fixed-case">PC</jats:styled-content>a remain elusive. Here, we show that in contrast to many other tumors, <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 <jats:styled-content style="fixed-case">mRNA</jats:styled-content> and protein levels were decreased in 80% of <jats:styled-content style="fixed-case">PC</jats:styled-content>a in comparison with non‐neoplastic adjacent prostate and were independent of <jats:styled-content style="fixed-case">LOI</jats:styled-content> status. Instead, <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 expression in both tumors and adjacent prostate depended on preferential usage of the <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 promoters P3 and P4. Decreased <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 expression in tumors was strongly related to hypermethylation of these two promoters. Methylation of the A region in promoter P4 correlated specifically with <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 expression in the 20% of <jats:styled-content style="fixed-case">PC</jats:styled-content>a where <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 was higher in tumors than in adjacent prostate. We conclude that <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 is downregulated in most <jats:styled-content style="fixed-case">PC</jats:styled-content>a and may be particularly relevant during early stages of tumor development or during chemotherapy and androgen deprivation. <jats:styled-content style="fixed-case">PC</jats:styled-content>a differs from other tumors in that <jats:styled-content style="fixed-case">IGF</jats:styled-content>2 expression is mainly regulated through methylation of promoter‐specific and not by imprinting. Targeting of promoter‐specific regions may have relevance for the adjuvant treatment of <jats:styled-content style="fixed-case">PC</jats:styled-content>a.</jats:p>