Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors

Abstract

How hypermethylation and hypomethylation of different parts of the genome in cancer are related to each other and to DNA methyltransferase (DNMT) gene expression is ill defined. We used ovarian epithelial tumors of different malignant potential to look for associations between 5 0 -gene region or promoter hypermethylation, satellite, or global DNA hypomethylation, and RNA levels for ten DNMT isoforms. In the quantitative MethyLight assay, six of the 55 examined gene loci (LTB4R, MTHFR, CDH13, PGR, CDH1, and IGSF4) were significantly hypermethylated relative to the degree of malignancy (after adjustment for multiple comparisons; Po0.001). Importantly, hypermethylation of these genes was associated with degree of malignancy independently of the association of satellite or global DNA hypomethylation with degree of malignancy. Cancer-related increases in methylation of only two studied genes, LTB4R and MTHFR, which were appreciably methylated even in control tissues, were associated with DNMT1 RNA levels. Cancer-linked satellite DNA hypomethylation was independent of RNA levels for all DNMT3B isoforms, despite the ICF syndrome-linked DNMT3B deficiency causing juxtacentromeric satellite DNA hypomethylation. Our results suggest that there is not a simple association of gene hypermethylation in cancer with altered DNMT RNA levels, and that this hypermethylation is neither the result nor the cause of satellite and global DNA hypomethylation.

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

“…All these genes were overexpressed in NSCLC tissues, in concordance with previous reports in other human cancer types. [17][18][19]21,47,48 A strong correlation between the expression levels of all the DNMTs was observed, in accordance with a reported coordinated expression of DNMTs. 22,47 Furthermore, the expression levels of all DNMTs examined in this set was correlated with the expression of E2F1.…”

“…14 In addition, there is increasing evidence suggesting the involvement of histone modifications and nucleosome positioning in both de novo and maintenance methylation processes. 15,16 Numerous studies have demonstrated frequent overexpression of the DNMTs in many cancer types, [17][18][19] which in some cases correlated with the hypermethylation of particular TSGs. [20][21][22] However, other reports suggest that DNMT overexpression does not by itself seem to sufficiently account for the hypermethylation of TSG promoters.…”

“…[20][21][22] However, other reports suggest that DNMT overexpression does not by itself seem to sufficiently account for the hypermethylation of TSG promoters. 19,21,23,24 UHRF1 (also known as ICBP90) has recently been shown to play an important role in methylation maintenance. 25 It has the ability to bind hemimethylated DNA through its SET-and RING-associated domain, 26,27 triggering the recruitment of DNMT1 25,28 and histone deacetylace-1.…”

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

“…Gene hypermethylation and satellite and global DNA hypomethylation in ovarian tumours are both independently associated with the degree of malignancy 46. Satellite DNA hypomethylation is significantly more prevalent in advanced‐stage and high‐grade ovarian cancers and is an independent marker of poor prognosis 47.…”

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

“…Mutations of the DNMT genes are rare in cancer cells (Kanai et al, 2003). Several groups have examined the expression of DNMT transcripts and have not found a correlation with DNA methylation levels in cancer cells (Robertson et al, 1999;Saito et al, 2002;Ehrlich et al, 2006). However, expression of transcripts that originate from a promoter within intron 4, DDNMT3B1-7, correlates with the DNA methylation states of the p16 and RASSF1A promoters in non-small-cell lung cancers (Wang et al, 2006a).…”