EpiGenie ran recently ran a review of the new text Epigenetics: A Reference Manual. Now, to present a little taste of what the book has to offer, here’s a summary of one of the chapters.
DNA Methylation Changes in Cancer
By Samson Mani and Zdenko Herceg
Epigenetic mechanisms can contribute to each step of cancer development and progression; DNA methylation (reversible) is the dominant factor that is deregulated in cancer. DNA methylation is a reversible process which typically occurs at CpG dinucleotides. In normal cells CpG islands (mostly in gene promoter regions) are unmethylated, and repetitive elements and transposons are mostly methylated. DNA methylation is achieved by DNA methyltransferases (DNMTs) and interferes with gene transcription in several ways. A direct impact on gene transcription is by inhibition of binding of transcription factors to target sequences by methylation CpGs. DNA methylation can also indirectly interfere with gene transcription via proteins that bind to methylated CpGs (such as MeCP2) and hereby block binding of transcription factors to these sites. Deregulation of DNMTs has been found in different cancers, leading to DNA methylation changes.
Knockout studies in mice have shown that loss of DNMT1 (the maintenance methyltransferase) and DNMT3B (de novo methylation) leads to a complete loss of DNA methylation and a severe reduction in cell growth. Methylation of CpG islands in promoter regions of imprinted genes is responsible for allele-specific expression. DNA methylation changes have also been found to affect chromatin structure by their interactions with histone modification enzymes (such as HDACs) and hence gene expression patterns. Differential histone modification patterns have also directly been associated with disease, such as specific heterochromatic regions in acute lymphoblastic leukemia (ALL).
Common DNA methylation changes in cancer:
- Global hypomethylation leads to activation of oncogenes, transposition of repetitive elements, chromosomal instability. Common in solid tumors. Examples of hypomethylated sequences are LINEs, c-MYC, H-RAS.
- Gene promoter-specific hypermethylation initiates loss of function (gene inactivation) of tumor suppressor genes due to promoter CpG island methylation. Examples of specific genes that become methylated in different cancers are RB1, VHL, CDKN2A, hMLH1, BRCA1, APC. Some hypermethylated genes have been indicated as biomarkers because of their changed methylation status, such as DAKP1, RARβ and TWIST1 (cervical cancer) and GSTP1 (prostate cancer).
- Methylation of miRNA promoter regions, changing miRNA expression profiles and indirectly the expression of their targets.
DNA methylation changes contribute directly to tumorigenesis and detection of these changes can be used for early diagnosis or disease monitoring and prognosis. Solid tumors release cells and DNA fragments into the blood stream and these can be used as surrogate markers for metastatic tumors. Sophisticated techniques detecting methylated DNA sequences or tumor cells allow studying methylation profiles and possible prognostic factors in various types of cancer. Also, many of the molecules involved in epigenetic processes are possible targets for new therapies.
This chapter summary was provided courtesy of Anne Benard who is currently a PhD student at the John Wayne Cancer Institute in Santa Monica, CA,
You can get yourself a copy of Epigenetics: A Reference Manual at the Horizon Press website.