Research Area

Cancer Epigenetics


Introduction of Epigenetics

Epigenetics is the study of heritable changes in gene function that do not involve changes in the DNA sequence. A variety of epigenetic mechanisms can be perturbed in different types of cancer. Epigenetic alterations of DNA repair genes or cell cycle control genes are very frequent in sporadic (non-germ line) cancers, being significantly more common than germ line (familial) mutations in these sporadic cancers. So researchers think that epigenetic alterations may be just as important, or even more worthy, than genetic mutations in a cell's transformation to cancer. So far, the mechanisms of epigenetic is the covalent modifications(covalent modifications of either DNA (e.g. cytosine methylation(CpG) and hydroxymethylation) or of histone proteins (e.g. lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation).), RNA transcripts(include: recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci; the production of different splice forms of RNA; formation of double-stranded RNA (RNAi)), MicroRNAs, the modification of mRNA, sRNAs, Prions and so on. In cancers, loss of expression of genes occurs about 10 times more frequently by transcription silencing (caused by epigenetic promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. Several medications which have epigenetic impact are now employed in several of these diseases.

Introduction of Epigenetics

Mechanisms of Cancer Epigenetics

According to previous studies, epigenetics alterations play an important role in tumorigenesis by DNA methylation, histone modification and MicroRNA gene silencing.

  • DNA Methylation

In somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with high fidelity. However, epigenetic DNA methylation differs between normal cells and tumor cells in humans. The "normal" CpG methylation profile is often inverted in cells that become tumorigenic. In normal cells, CpG islands preceding gene promoters are generally unmethylated, and tend to be transcriptionally active, while other individual CpG dinucleotides throughout the genome tend to be methylated. However, in cancer cells, CpG islands preceding tumor suppressor gene promoters are often hypermethylated, while CpG methylation of oncogene promoter regions and parasitic repeat sequences is often decreased. Hypermethylation of tumor suppressor gene promoter regions can result in the silencing of those genes. This type of epigenetic mutation allows cells to grow and reproduce uncontrollably, leading to tumorigenesis. Studies show that some genes of relation with DNA repair and cell cycle is silenced by the promoter hypermethlation. Such as: p16, MGMT, APC, MLH1, BRCA1. Meanwhile, hypomethylation of CpG dinucleotides in other parts of the genome leads to chromosome instability due to mechanisms such as loss of imprinting and reactivation of transposable elements. So the entire genome of a cancerous cell contains significantly less methylcytosine than the genome of a healthy cell by disruption in DNA methyltransferases. And then, "global hypomethylation" may promote mitotic recombination and chromosome rearrangement, ultimately resulting in aneuploidy when the chromosomes fail to separate properly during mitosis.

  • Histone Modification

Studies show that eukaryotic DNA has a complex structure. It is generally wrapped around special proteins called histones to form a structure called a nucleosome. A nucleosome consists of 2 sets of 4 histones: H2A, H2B, H3, and H4. Additionally, histone H1 contributes to DNA packaging outside of the nucleosome. Certain histone modifying enzymes can add or remove functional groups to the histones, and these modifications influence the level of transcription of genes wrapped around those histones and the level of DNA replication. Compare with common cells, researches find that histone modification profiles of healthy and cancerous cells tend to differ. In comparison to healthy cells, cancerous cells exhibit decreased monoacetylated and trimethylated forms of histone H4. In mouse models, the loss of histone H4 acetylation and trimethylation increases as tumor growth continues. In addition, other histone marks associated with tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 (H3K4me3), and increased monomethylation of histone H3 Lysine 9 (H3K9me) and trimethylation of histone H3 Lysine 27 (H3K27me3). These histone modifications can silence tumor suppressor genes despite the drop in methylation of the gene's CpG islands (an event that normally activates genes).

The tumor suppressor gene p53 regulates DNA repair and can induce apoptosis in dysregulated cells. So it is a key role in tumorigenesis. According to previous studies, the CTCF protein(a zinc finger protein) can regulate p53 expression by insulating the p53 promoter from accumulating repressive histone marks. Besides, mutations in the epigenetic machinery also infect the tumorigenesis by altering chromatin structure.

  • MicroRNA Gene Silencing

MicroRNAs (miRNAs) are members of non-coding RNAs that range in size from 17 to 25 nucleotides. In mammals, microRNAs (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes. It's worth noting that some miRNA as a tumor suppressor, such as, miR-125b1. Interestingly, miR-125b1 can be silenced by DNA methylation. In patients with breast cancer, hypermethylation of CpG islands located proximal to the transcription start site was observed. In addition, loss of CTCF(CTCF may function as a boundary element to stop the spread of DNA methylation) binding and an increase in repressive histone marks, H3K9me3 and H3K27me3, correlates with DNA methylation and miR-125b1 silencing.

  • Clinical Significance

Epigenetic control of the proto oncogene regions and the tumor suppressor sequences by conformational changes in histones plays a role in the formation and progression of cancer. Pharmaceuticals that reverse epigenetic changes might have a role to play in a variety of cancers. Recently, it is evidently known that associations between specific cancer histotypes and epigenetic changes can facilitate the development of novel epi-drugs. Drug development has focused mainly on modifying DNA methyltransferase, histone acetyltransferase (HAT) and histone deacetylase (HDAC).

Drugs that specifically target the inverted methylation pattern of cancerous cells include the DNA methyltransferase inhibitors azacitidine and decitabine. These hypomethylating agents are used to treat myelodysplastic syndrome, a blood cancer produced by abnormal bone marrow stem cells. These agents inhibit all three types of active DNA methyltransferases, and had been thought to be highly toxic, but proved to be helpful when used in low dosage, reducing progression of myelodysplastic syndrome to leukemia.

Histone deacetylase (HDAC) inhibitors show efficacy in treatment of T cell lymphoma. However, since these HDAC inhibitors alter the acetylation state of many proteins in addition to the histone of interest, knowledge of the underlying mechanism at the molecular level of patient response is required to enhance the efficiency of using such inhibitors as treatment. Treatment with HDAC inhibitors has been proven to promote gene reactivation after DNA methyltransferases inhibitors have repressed transcription.

References:

  1. Dupont C., Armant DR., Brenner C.A., Epigenetics: definition, mechanisms and clinical perspective. Seminars in Reproductive Medicine. 2009, 27 (5): 351–357.
  2. Vogelstein B., et al. Cancer genome landscapes. Science. 2013, 339 (6127): 1546–58.
  3. Novak, Kris. Epigenetics Changes in Cancer Cells. Medscape General Medicine. 2004, 6 (4): 17.
  4. Steller M., Cancer epigenomics: DNA methylomes and histone-modification maps. Nature Reviews Genetics. 2007, 8 (4): 286–98.
  5. Herman J.G., Baylin S.B., Gene silencing in cancer in association with promoter hypermethylation. The New England Journal of Medicine. 2003, 349 (21): 2042–54.
  6. Singh P., et al. Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers. Mol. Cancer Res. 2008, 6 (11): 1710–7.
  7. Li D., et al. Poly (ADP-ribose) polymerase 1 transcriptional regulation: a novel crosstalk between histone modification H3K9ac and ETS1 motif hypomethylation in BRCA1-mutated ovarian cancer. Oncotarget. 2014, 5 (1): 291–7.
  8. Garcia M. G., Demethylating agents in myeloid malignancies. Curr Opin Oncol. 2008, 20 (6): 705–10.
  9. Iglesias L. A., et al. Potential role of HDAC inhibitors in cancer therapy: insights into oral squamous cell carcinoma. Oral Oncol. 2010, 46 (5): 323–9.
  10. Cameron E.E., et al. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genetics. 1999, 21 (1): 103–7.

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