What Causes DNA Demethylation in Tumors?

[DB]

Tumors are caused by the demethylation of DNA sections. But what causes the demethylation?

Thanks

 

[bross7]

I can't quite explain this in any way but I thought that, for instance in breast cancer, it is possible that the cancer is caused by the methlyation of DNA, not the DNA demethylation. The methylation has an effect on inhibiting transcription machinery, and in this case on tumor suppressor genes.

If I am wrong, is there someone who can clarify this.

 

[iansmith]

Methylation in the promotor region plays a role in transcription level. CpG island are often associated with methylation.

In mammalians, demethylation of specific promoter regions often correlates with gene activation; inversely, dense methylation of CpG islands leads to gene silencing, probably mediated by methyl-CpG binding proteins.

http://www.fasebj.org/cgi/content/abstract/14/11/1585

Regarding cancer, the gene with the inappropriate transcription level will influence the result. For example, demethylation of a tumor promoting gene will lead in cancer due to increase level of the tumor-promoting protein. The methylation of tumor suppressor genes will also lead to cancer but due the repression of a tumor suppressor gene.

 

[iansmith]

Demethylation is a normal process of gene transcription; however, defective DNA repair pathway or error made the DNA transcritption machinery will lead to prolonged demethylation.

http://embojournal.npgjournals.com/cgi/content/full/17/5/1446

 

[Chronos]

Demethylation is the symptom, not the cause. Faulty receptors do not recognize the signal. Active receptors get overstimulated and assumes the signal means they should do something - even if its wrong. And it usually is wrong. A cascading response typically follows.

 

[Moonbear]

There are enzymes activated that regulate methylation, DNA methyltransferases, and their absence or suppression can lead to reduced methylation. Depending on the region of the genome, hypo- or hypermethylation can affect tumor formation. As iansmith pointed out, methylation is important for transcriptional regulation, so alterations in either direction can lead to errors in important regulatory steps and promote tumorigenesis.

Here are two abstracts, selected somewhat randomly from the literature addressing this, that serve to illustrate the point (I didn't choose these because they are any better or more relevant than any number of papers out there, but because the abstract contains enough information to illustrate the point if you can't get to the full text of the article).

Cancer Biol Ther. 2004 Nov 9;3(11)

DNA Hypomethylation Is Prevalent Even in Low-Grade Breast Cancers.

Jackson K, Yu MC, Arakawa K, Fiala E, Youn B, Fiegl H, Muller-Holzner E, Widschwendter M, Ehrlich M.

Hypomethylation of some portions of the genome and hypermethylation of others are very frequent attributes of human cancer. We previously showed that cancer-associated DNA hypomethylation often involves satellite 2 (Sat2), the main DNA component of the large juxtacentromeric (centromere-adjacent) heterochromatin of chromosome 1. In this study, we compared methylation of Sat2 and centromeric satellite DNA (Satalpha) as well as overall genomic methylation in 41 breast adenocarcinomas of known tumor grade and stage, 16 non-neoplastic breast tissues (mostly fibroadenomas), and a variety of normal somatic tissue controls. The cancers were significantly hypomethylated at Sat2 relative to the fibroadenomas or normal somatic tissues and at Satalpha relative to the normal somatic tissues. However, unlike Sat2, Satalpha did not display significant differences in methylation between the cancers and the non-neoplastic breast tissues. Therefore, hypomethylation at Sat2 is a much better marker of breast cancer than is Satalpha hypomethylation. There was a significant association of Sat2 hypomethylation with global DNA hypomethylation in the cancers but not with tumor grade, stage, axillary lymph node involvement, or hormone receptor status. Extensive cancer-associated hypomethylation of juxtacentromeric satellite DNA and global DNA hypomethylation were common even in grade-1 or stage-1 carcinomas, which suggests that demethylation of the genome is an early event in breast carcinogenesis.

J Pharmacol Exp Ther. 2005 Feb;312(2):525-36.

5-aza-Cytidine Is a Potent Inhibitor of DNA Methyltransferase 3a and Induces Apoptosis in HCT-116 Colon Cancer Cells via Gadd45- and p53-Dependent Mechanisms.

Schneider-Stock R, Diab-Assef M, Rohrbeck A, Foltzer-Jourdainne C, Boltze C, Hartig R, Schonfeld P, Roessner A, Gali-Muhtasib H.

Methyltransferase inhibitors commonly used in clinical trials promote tumor cell death, but their detailed cytotoxic action is not yet fully understood. A deeper knowledge about their apotosis-inducing mechanisms and their interaction with DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b might allow the design of more effective drugs with lower cytotoxicity. 5-aza-cytidine (5-aza-CR), a potent inhibitor of DNMT1, is known to induce demethylation and reactivation of silenced genes. In this study, we investigated the p53 dependence of apoptotic, cell cycle, and growth inhibitory effects of 5-aza-CR, as well as the influence on the expression level of DNMT1, DNMT3a, and DNMT3b in the colon cancer cell line HCT-116. Exposure to 5-aza-CR induced the up-regulation of genes promoting cell cycle arrest and DNA repair (p21(WAF1) and GADD45) or apoptosis (p53, RIPK2, Bak1, caspase 5, and caspase 6). In parallel, there was a down-regulation of antiapoptotic Bcl2 protein and the G(2)/M-mediator cyclin B1. Co-incubation with pifithrin-alpha (PFT-alpha), a selective p53 inhibitor, restored GADD45, Bcl2, cyclin B1, and p21(WAF1) expression levels and almost completely reversed the growth inhibitory, cell cycle, and apoptotic effects of 5-aza-CR. 5-aza-CR treatment caused global demethylation and reactivation of p16(INK4) expression. There was a marked decrease in DNMT1 and DNMT3a mRNA expression, with PFT-alpha reversing these effects. However, 5-aza-CR treatment did not modulate DNMT3b expression. Our data demonstrate that 5-aza-CR action in HCT-116 is mediated by p53 and its downstream effectors p21(WAF1) and GADD45. This is the first report to show a link between p53 and regulation of DNMT1 and de novo methyltransferase DNMT3a.