The loss of NKX3.1 expression in testicular – and prostate – cancers is not caused by promoter hypermethylation

Down-regulation of NKX3.1 expression was generally not caused by promoter hypermethylation, which was only found in one TGCT. However, other epigenetic mechanisms, such as modulation of chromatin structure or modifications of histones, may explain the lack of NKX3.1 expression, which is seen in most TGCTs and prostate cancer specimens.The protein expression of the homeobox gene NK3 transcription factor related locus 1 (NKX3.1) is highly specific for the prostate and the testis [1-3], and is frequently lost in cancers of these two tissue types [1,4,5]. NKX3.1 is located in chromosome band 8p21 [2,6,7], a region that undergoes frequent allelic imbalance in prostatic intraepithelial neoplasia (PIN) and prostate carcinomas [8,9]. In mice, targeted disruption of Nkx3.1 leads to prostatic epithelial hyperplasia and dysplasia [10,11], and over-expression of exogenous NKX3.1 suppresses growth and tumorigenicity in human prostate carcinoma cell lines [12]. However, the expression levels and possible role for NKX3.1 during prostate cancer progression in humans is still being debated [13-15]. No gene mutations of NKX3.1 have been found [6], and NXK3.1 is therefore believed to be epigenetically inactivated in the cases with loss of protein expression [1,5,16]. Only one study has reported NKX3.1 protein expression in testicular germ cell tumors (TGCTs), however the series analyzed was large, including a total of more than 500 samples, and NKX3.1 was found absent in all embryonal carcinomas and present in only 15–20% of the seminomas as well as among the differentiated histological subtypes of germ cell tumors [5].During the last decade, epigenetic changes in cancer have been frequently reported and are now recognized to be at least as common as genetic changes [17]. The best characterized epigenetic mechanism is DNA hypermethylation, in which cytosines located within selected CpG sites in the gene promoters become methylated, thereby inactivating gene expression. Several tumor s