Decitabine—Bedside to bench

Oki, Yasuhiro; Aoki, Etsuko; Issa, Jean–Pierre J.

doi:10.1016/j.critrevonc.2006.07.010

Cited by 152 publications

(125 citation statements)

References 78 publications

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“…To date, investigations have focused on the use of the cytidine analogue DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR), which is an FDA approved drug (decitabine) used for the treatment of myelodysplastic anaemia (Oki et al, 2007). Treatment of fully methylated FRAXA patient cell lines with 5-aza-CdR leads to a decrease in promoter CpG methylation, together with increased histone acetylation, decreased H3K9 methylation and increased H3K4 methylation, that result in an increase in FMR1 transcription (Chiurazzi et al, 1998;Pietrobono et al, 2002;Tabolacci et al, 2005).…”

Section: Demethylation Therapy For Tnr Expansion Diseasesmentioning

confidence: 99%

DNA Methylation and Trinucleotide Repeat Expansion Diseases

Pook¹

2012

DNA Methylation - From Genomics to Technology

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Section: Demethylation Therapy For Tnr Expansion Diseasesmentioning

confidence: 99%

DNA Methylation and Trinucleotide Repeat Expansion Diseases

Pook¹

2012

DNA Methylation - From Genomics to Technology

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“…In contrast to genetic mutations, which are essentially irreversible, DNA hypermethylation can be pharmacologically reversed by using small compounds (Yoo and Jones, 2006) that inhibit the activity of DNA methyltransferases (DNMTs), the enzymes that catalyse the transfer of a methyl group to the 5 0 -position of cytosines (Jones and Baylin, 2007;Esteller, 2008). The existence of such inhibitors has stimulated intense research because of their potential use as chemotherapeutics, and several DNMT inhibitors have recently been approved for the clinical treatment of cancer (Oki et al, 2007;GarciaManero, 2008).…”

Section: Introductionmentioning

confidence: 99%

Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation

2009

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Understanding the mechanisms that link changes in DNA methylation with histone modifications is particularly relevant in the case of tumor suppressor genes that undergo transcriptional silencing in cancer cells in association with promoter CpG island hypermethylation. In this study, we show that two histone lysine methylation marks associated with active transcription, dimethylation of H3K79 (H3K79me2) and trimethylation of H3K4 (H3K4me3), are present in all the unmethylated promoters analysed, and both of them are lost when these promoters become hypermethylated. Most importantly, pharmacological and genetic interventions that cause DNA demethylation and partial recovery of gene transcription, result in the restoration of H3K4me3, but not of H3K79me2. We also show that DOT1L, the major H3K79 histone methyltransferase, is no longer recruited to the promoters that are demethylated after 5-azadeoxycytidine treatment or genetic deletion of DNA methyltransferases. Knock-down and transfection experiments for DOT1L show that this enzyme has a direct role in maintaining the euchromatic and active status of these genes when unmethylated. These findings suggest that DNA demethylating interventions alone are not able to restore a complete euchromatic status and a full transcriptional reactivation of the epigenetically silenced tumor suppressor genes, and reinforce the necessity of targeting multiple elements of the epigenetics machinery for a successful treatment of malignancies.

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“…Indeed, MSP is a simple, highly sensitive and nonquantitative test. A minimal degree of methylation can be registered as "positive methylation" depending on the original DNA concentration, primer sets, and the number of cycles used for PCR (46,47).…”

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confidence: 99%

Status of p16<SUP>INK4a</SUP> and E-Cadherin Gene Promoter Methylation in Moroccan Patients With Cervical Carcinoma

Attaleb¹,

W²,

Khyatti³

et al. 2009

oncol res

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Aberrant methylation of tumor suppressor gene promoters has been extensively investigated in cervical cancer. Transcriptional silencing, as a main consequence of hypermethylation of CpG islands, is the predominant mechanism of p16 INK4a and E-cadherin gene inactivation in malignant epithelial tumors. This study was conducted to evaluate the promoter methylation status of p16 INK4a and E-cadherin genes in 22 specimens of cervical carcinomas, four cervical cancer cell lines (HeLa, SiHa, Caski, C33A), and 20 human papillomavirus negative specimens, obtained from normal cervical swabs, using the methylation-specific PCR approach. Hypermethylation of the 5′ CpG island of the p16 INK4a and E-cadherin genes were found in 13 (59.1%) and 10 (45.5%) of 22 cervical cancer samples, respectively. Furthermore, our findings did not show any correlation between promoter methylation of p16 INK4a and E-cadherin genes and clinicopathological parameters, including HPV infection, phenotypic distribution, and stage of the disease. However, hypermethylation of E-cadherin gene promoter appears to be age related in cervical cancer, whereas the frequency of aberrant methylation of p16 INK4a gene promoter is unchanged according to the age of patients. Thus, caution must be made to use these markers in the diagnosis of cervical cancer. However, dietary or pharmaceutical agents that can inhibit these epigenetic events may prevent or delay the development of cervical cancer.

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Decitabine—Bedside to bench

Cited by 152 publications

References 78 publications

DNA Methylation and Trinucleotide Repeat Expansion Diseases

DNA Methylation and Trinucleotide Repeat Expansion Diseases

Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation

Status of p16<SUP>INK4a</SUP> and E-Cadherin Gene Promoter Methylation in Moroccan Patients With Cervical Carcinoma

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