CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.
TLDR
Basic and translational studies will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer.Abstract:
We have come a long way since the first reports of the existence of aberrant DNA methylation in human cancer. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. CpG island hypermethylation has been described in almost every tumor type. Many cellular pathways are inactivated by this type of epigenetic lesion: DNA repair (hMLH1, MGMT), cell cycle (p16INK4a, p15INK4b, p14ARF), apoptosis (DAPK), cell adherence (CDH1, CDH13), detoxification (GSTP1), etc … However, we still know little of the mechanisms of aberrant methylation and why certain genes are selected over others. Hypermethylation is not an isolated layer of epigenetic control, but is linked to the other pieces of the puzzle such as methyl-binding proteins, DNA methyltransferases and histone deacetylase, but our understanding of the degree of specificity of these epigenetic layers in the silencing of specific tumor suppressor genes remains incomplete. The explosion of user-friendly technologies has given rise to a rapidly increasing list of hypermethylated genes. Careful functional and genetic studies are necessary to determine which hypermethylation events are truly relevant for human tumorigenesis. The development of CpG island hypermethylation profiles for every form of human tumors has yielded valuable pilot clinical data in monitoring and treating cancer patients based in our knowledge of DNA methylation. Basic and translational will both be needed in the near future to fully understand the mechanisms, roles and uses of CpG island hypermethylation in human cancer. The expectations are high.read more
Citations
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Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia
George A. Calin,Calin Dan Dumitru,Masayoshi Shimizu,Roberta Bichi,Simona Zupo,Evan Noch,Hansjuerg Aldler,Sashi Rattan,Michael J. Keating,Kanti R. Rai,Laura Z. Rassenti,Thomas J. Kipps,Massimo Negrini,Florencia Bullrich,Carlo M. Croce +14 more
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Anna Portela,Manel Esteller +1 more
TL;DR: A comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research.
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Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer
Mario F. Fraga,Esteban Ballestar,Ana Villar-Garea,Manuel Boix-Chornet,Jesús Espada,Gunnar Schotta,Tiziana Bonaldi,Claire E. Haydon,Santiago Ropero,Kevin Petrie,N. Gopalakrishna Iyer,Alberto Pérez-Rosado,Enrique Calvo,Juan Antonio López,Amparo Cano,María José Calasanz,Dolors Colomer,Miguel A. Piris,Natalie G. Ahn,Natalie G. Ahn,Axel Imhof,Carlos Caldas,Thomas Jenuwein,Manel Esteller +23 more
TL;DR: It is found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4 early and accumulated during the tumorigenic process, which is a common hallmark of human tumor cells.
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Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis
TL;DR: The Beta-value has a more intuitive biological interpretation, but the M-value is more statistically valid for the differential analysis of methylation levels, and is recommended for conducting differential methylation analysis and including the beta-value statistics when reporting the results to investigators.
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The power and the promise of DNA methylation markers
TL;DR: The past few years have seen an explosion of interest in the epigenetics of cancer as a consequence of both the exciting coalescence of the chromatin and DNA methylation fields, and the realization thatDNA methylation changes are involved in human malignancies.
References
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Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands
TL;DR: The use of MSP is demonstrated to identify promoter region hypermethylation changes associated with transcriptional inactivation in four important tumor suppressor genes (p16, p15, E-cadherin and von Hippel-Lindau) in human cancer.
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CpG-rich islands and the function of DNA methylation
TL;DR: It is likely that most vertebrate genes are associated with ‘HTF islands’—DNA sequences in which CpG is abundant and non-methylated; however, highly tissue-specific genes, though, usually lack islands.
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Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex
Xinsheng Nan,Huck-Hui Ng,Colin A. Johnson,Carol D. Laherty,Bryan M. Turner,Robert N. Eisenman,Adrian Bird +6 more
TL;DR: The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis.
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Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.
Peter L. Jones,Gert C. Jan Veenstra,Paul A. Wade,Danielle Vermaak,Stefan U. Kass,Nicoletta Landsberger,John Strouboulis,Alan P. Wolffe +7 more
TL;DR: The results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.
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Cancer-epigenetics comes of age
Peter A. Jones,Peter W. Laird +1 more
TL;DR: Current mechanistic understanding of the role of DNA methylation in malignant transformation is reviewed, and it is suggested Knudson's two–hit hypothesis should be expanded to include epigenetic mechanisms of gene inactivation.