Open AccessInsulin‐like growth factor 2 expression in prostate cancer is regulated by promoter‐specific methylation
Author(s) -
Küffer Stefan,
Gutting Tobias,
Belharazem Djeda,
Sauer Christian,
Michel Maurice S.,
Marx Alexander,
Trojan Lutz,
Ströbel Philipp
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12164
Subject(s) - prostate cancer , cancer research , insulin like growth factor , dna methylation , biology , insulin like growth factor 2 , growth factor , promoter , prostate , methylation , epigenetics , cancer , gene expression , endocrinology , medicine , gene , genetics , receptor
Deregulation of the insulin‐like growth factor ( IGF ) axis and dysbalance of components of the IGF system as potential therapeutic targets have been described in different tumor types. IGF 2 is a major embryonic growth factor and an important activator of IGF 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 ( PC a). Loss of imprinting ( LOI ) usually results in bi‐allelic gene expression and increased levels of IGF 2. However, the regulatory mechanisms and the pathophysiological impact of altered IGF 2 expression in PC a remain elusive. Here, we show that in contrast to many other tumors, IGF 2 mRNA and protein levels were decreased in 80% of PC a in comparison with non‐neoplastic adjacent prostate and were independent of LOI status. Instead, IGF 2 expression in both tumors and adjacent prostate depended on preferential usage of the IGF 2 promoters P3 and P4. Decreased IGF 2 expression in tumors was strongly related to hypermethylation of these two promoters. Methylation of the A region in promoter P4 correlated specifically with IGF 2 expression in the 20% of PC a where IGF 2 was higher in tumors than in adjacent prostate. We conclude that IGF 2 is downregulated in most PC a and may be particularly relevant during early stages of tumor development or during chemotherapy and androgen deprivation. PC a differs from other tumors in that IGF 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 PC a.