Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases.

@article{Paz2003GeneticUO,
  title={Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases.},
  author={Maria fe Paz and Susan H. Wei and Juan C. Cigudosa and Sandra Rodr{\'i}guez-Perales and Miguel A. Peinado and Tim Hui-Ming Huang and Manel Esteller},
  journal={Human molecular genetics},
  year={2003},
  volume={12 17},
  pages={
          2209-19
        }
}
Hypermethylation associated silencing of the CpG islands of tumor suppressor genes is a common hallmark of human cancer. Here we report a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKO cells). Using two molecular screenings for differentially methylated loci [differential methylation hybridization (DMH) and amplification of inter-methylated sites… 

Figures and Tables from this paper

How CpG Island Hypermethylation Leads to Cancer Dissemination: The Sounds of Silence for Tumor and Metastasis Suppressor Genes
TLDR
Preliminary data suggest that DNA demethylating drugs, reactivating these dormant methylated metastasis genes, have an effect against the development of metastasis.
DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers
TLDR
It is found that DLEC1 is a functional tumour suppressor, being frequently silenced by epigenetic mechanism in gastrointestinal tumours.
Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma.
TLDR
It is shown that other members of the TSPYL gene family are epigenetically silenced in gliomas and dissect the contribution of individual DNA methyltransferases to the aberrant promoter hypermethylation events.
Genetic unmasking of an epigenetically silenced microRNA in human cancer cells.
TLDR
Interestingly, this work functionally link the epigenetic loss of miRNA-124a with the activation of cyclin D kinase 6, a bona fide oncogenic factor, and the phosphorylation of the retinoblastoma, a tumor suppressor gene.
Epigenetics provides a new generation of oncogenes and tumour-suppressor genes
TLDR
‘New’ oncogenes and tumour-suppressor genes provide novel molecular targets for designed therapies, and the first DNA-demethylating agents and inhibitors of histone deacetylases are reaching the bedside of patients with haematological malignancies.
Decitabine treatment demethylates vast majority of high-confidence differentially methylated regions in HCT-116 colorectal cancer cells
TLDR
This study used bioinformatics and bisulfite PCR sequencing to investigate methylation levels at DMRs in the promoters of six genes and revealed hypermethylated CpG sites not shown by previous genome-wide methylation studies.
Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers
TLDR
Aberrantly methylated DNA fragments were searched for in human pancreatic cancers, using the genome scanning technique: methylation-sensitive-representational difference analysis (MS-RDA), and some were suggested to be potentially involved in pancreatic cancer development and progression.
Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers.
TLDR
Small interfering RNA-mediated knockdown of RELN in pancreatic cancer cells that retain RELN expression resulted in greatly enhanced cell motility, invasiveness, and colony-forming ability, suggesting the importance of this pathway as a diagnostic and therapeutic target for pancreatic cancers.
...
...

References

SHOWING 1-10 OF 41 REFERENCES
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.
DNMT1 and DNMT3b cooperate to silence genes in human cancer cells
TLDR
It is demonstrated that two enzymes cooperatively maintain DNA methylation and gene silencing in human cancer cells, and compelling evidence that such methylation is essential for optimal neoplastic proliferation is provided.
Methylation profiling of CpG islands in human breast cancer cells.
TLDR
This study provides evidence that, aside from random DNA-MTase action, additional cellular factors exist that govern aberrant methylation in breast cancer cells.
CpG methylation is maintained in human cancer cells lacking DNMT1
TLDR
It is shown that cells lacking DNMT1 exhibited markedly decreased cellular DNA methyltransferase activity, but there was only a 20% decrease in overall genomic methylation, indicating thatDNMT1 has an unsuspected degree of regional specificity in human cells and that methylating activities other than DN MT1 can maintain the methylation of most of the genome.
DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells
TLDR
Results indicate that DNMT1 is necessary and sufficient to maintain global methylation and aberrant CpG island methylation in human cancer cells.
A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer
TLDR
Using cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer shows that this approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone.
Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays.
TLDR
The notion that hypermethylation of critical CpG island loci influences cancer development and produces distinct epigenetic signatures for particular tumor subtypes is supported.
A gene hypermethylation profile of human cancer.
TLDR
An unusual view of the pervasiveness of DNA alterations, in this case an epigenetic change, in human cancer is provided and a powerful set of markers are provided to outline the disruption of critical pathways in tumorigenesis and for derivation of sensitive molecular detection strategies for virtually every human tumor type.
Increased expression of unmethylated CDKN2D by 5-aza-2′-deoxycytidine in human lung cancer cells
TLDR
The data indicate that global DNA demethylation not only influences the expression of methylated genes but also of unmethylated genes and suggest that p19INK4d plays a distinct role from other INK4 family members in response to the cytotoxicity induced by inhibition of DNA methylation and histone deacetylation.
Genetic analyses of DNA methyltransferase genes in mouse model system.
TLDR
DNA methylation regulates important biological processes and is involved in tumorigenesis and several human diseases, such as Rett and immunodeficiency, centromeric instability and facial anomalies, through genetic analysis of DNA methyltransferase genes in mouse and human.
...
...