Promoter CpG hypermethylation and downregulation of DICE1 expression in prostate cancer

Abstract

A critical region of loss of heterozygosity on human chromosome 13q14 harbors the tumor suppressor gene DICE1 (DDX26). To elucidate the reduced DICE1 expression in tumor cells, the putative promoter sequence upstream of the DICE1 gene was analysed. This sequence shows a high GC content and is rich in CpG sites and binding sites of transcriptional factors. Promoter activity was identified within three overlapping fragments of the 800 bp sequence upstream of the DICE1 gene. A 13 bp deletion polymorphism detected in the DICE1 promoter region showed a decreased activity compared with the undeleted variant. However, this 13 bp deletion was seen in male control samples and patients with prostate cancer or benign prostatic hyperplasia at similar rates. A reduced DICE1 expression was observed in prostate cancer cell lines DU145 and LNCaP. This downregulation is associated with hypermethylation of the DICE1 promoter. Treatment of both prostate cancer cell lines with 5-azacytidine leads to upregulation of DICE1 expression. Hypermethylation of CpG sites of the DICE1 promoter was observed in four of eight analysed prostate cancers. This study suggests that transcriptional repression of DICE1 is caused by hypermethylation of the DICE1 promoter region in prostate cancer cells.

Deleted in cancer 1 (DICE1) is an essential protein controlling the topology of the inner mitochondrial membrane in C. elegans

“…Although DICE1 mRNA was detected in all human tissues, it was downregulated or absent in cell lines and tissues of non-small cell lung carcinoma. Hypermethylation of its promoter region was associated with its downregulation in several cell lines derived from non-small cell carcinomas (Wieland et al, 2001) and prostate cancers (Röpke et al, 2005). Ectopic expression of DICE1 inhibited colony formation by cell lines of both non-small cell lung cancer and prostate cancer, and suppressed anchorage-independent growth of mouse fibroblasts transformed with the IGF1 receptor gene (Wieland et al, 2004).…”

Opposing Roles of Dnmt1 in Early- and Late-Stage Murine Prostate Cancer

“…Analysis of the genes showing the greatest degree of hypermethylation in TRAMP; Dnmt1 ϩ/ϩ mice relative to TRAMP; Dnmt1 N/R mice at 24 weeks revealed that most of the hypermethylated regions are in promoter CpG islands (Table 3). With the exception of a small subset of these genes, including Csnk1g2, Ints6, and En1, most of the identified genes are not previously known to be regulated by DNA methylation (25,43,45).…”

Genetic Variants of DICE1/INTS6 in German Prostate Cancer Families with Linkage to 13q14

“…The coding sequence and adjacent splice sites of exons 1-18 of the DICE1 gene were directly sequenced with exon-specific primers as described previously [8] . Sequence analysis was performed as described [4] . Sequence variant c.2568A>G (p. S856S) was analyzed by exon 17 amplification and cleavage with Taq I (New England Biolabs GmbH, Frankfurt, Germany).…”

“…The gene deleted in cancer cells 1 ( DICE1; integrator complex subunit 6 INTS6 ; OMIM 604331) is located within this interval [2] . DICE1 was found to be frequently deleted in prostate cancer specimens [3,4] . A DICE1 missense mutation has been previously detected in prostate cancer cell line LNCap and reduced DICE1 expression appears to be associated with CpG promoter hypermethylation in prostate cancer cell lines [4,5] .…”

“…DICE1 was found to be frequently deleted in prostate cancer specimens [3,4] . A DICE1 missense mutation has been previously detected in prostate cancer cell line LNCap and reduced DICE1 expression appears to be associated with CpG promoter hypermethylation in prostate cancer cell lines [4,5] . All these suggest that the DICE1/INTS6 gene could be a putative prostate cancer-associated gene on 13q14.…”