The fundamental role of epigenetic events in cancer

Jones, Peter A.; Baylin, Stephen B.

doi:10.1038/nrg816

Cited by 4,816 publications

(4,131 citation statements)

References 91 publications

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“…Under hypoxic conditions, by contrast, significant numbers of apoptotic cells were detected following pretreatment with 5-aza-dC, which is indicative of the role played by epigenetic silencing of BNIP3 in protecting cells from hypoxia-mediated apoptosis. Methylation-dependent gene silencing is reportedly associated with altered chromatin structure involving deacetylation of histone (Jones and Baylin, 2002). Therefore, to assess the role of histone deacetylation in the silencing of BNIP3, we treated the methylated SupT1 cell line with 5-aza-dC and/or TSA, a histone deacetylase inhibitor ( Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with that finding, our ChIP assays showed histone H3 to be deacetylated in cell lines where BNIP3 is silent. It may be that dense methylation of the BNIP3 CpG island attracts methyl-CpG-binding proteins, such as MeCP2 and MBD2, which in turn recruit histone deacetylases (Jones and Baylin, 2002). Recent reports also suggest that histone methylation may be involved in DNA methylation-dependent gene silencing (Fahrner et al, 2002;Nguyen et al, 2002;Kondo and Issa, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

et al. 2005

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Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2 0 -deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5 0 region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5 0 CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

et al. 2005

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“…Epigenetic modifications play a significant role in tumor suppressor gene silencing and are potentially reversible (Jones and Baylin, 2002;Baylin and Ohm, 2006). Two of the best characterized epigenetic events are aberrant DNA methylation and changes in chromatin structure involving posttranslational modifications of histones (Yoo and Jones, 2006).…”

Section: Introductionmentioning

confidence: 99%

p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage

et al. 2008

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Decitabine (DAC) and 5-azacitidine have recently been approved for the treatment of myelodysplastic syndrome. The pharmacodynamic effects of DAC and 5-azacitidine outside their known activity as inhibitors of DNA methyltransferases (DNMTs) require further investigation. The purpose of this study was to investigate the effect of DAC on the expression of p21 WAF1/CIP1 , a gene with a putative CpG island surrounding its promoter region. Promoter methylation analysis of p21 WAF1/CIP1 in leukemia cells revealed the absence of CpG methylation. However, DAC upregulated p21 WAF1/CIP1 expression in a dosedependent manner (ED 50 ¼ 103.34 nM) and induced G2/M cell cycle arrest in leukemia cells. Sequential application of DAC followed by different histone deacetylase inhibitors induced expression of p21 WAF1/CIP1 synergistically. Upregulation of p21 WAF1/CIP1 paralleled DAC-induced apoptosis (ED 50 ¼ 153 nM). Low doses of DAC induced c-H2AX expression (ED 50 ¼ 16.5 nM) and upregulated p21 WAF1/CIP1 in congenic HCT 116 colon cancer cells in a DNMT-independent and p53-dependent fashion. Inhibition of p53 transactivation by pifithrin-a or the kinase activity of ATM by either the specific ATM inhibitor KU-5593 or caffeine abrogated p21 WAF1/CIP1 upregulation, indicating that DAC upregulation of p21 WAF1/CIP1 was p53-and ATM-dependent in leukemia cells. In conclusion, DAC upregulates p21 WAF1/CIP1 in DNMT-independent manner via the DNA damage/ATM/ p53 axis.

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“…DNA methylation and covalent modification of histone proteins are two epigenetic modifications important in transcriptional control (Jones and Baylin, 2002). Hypermethylation of CpG-rich sequences present in the promoters of genes is associated with gene silencing.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

et al. 2007

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To investigate the mechanism by which HSulf-1 expression is downregulated in ovarian cancer, DNA methylation and histone acetylation of HSulf-1 was analysed in ovarian cancer cell lines and primary tumors. Treatment of OV207 and SKOV3 by 5-aza-2 0 -deoxycytidine resulted in increased transcription of HSulf-1. Sequence analysis of bisulfite-modified genomic DNA from ovarian cell lines and primary tumors without HSulf-1 expression revealed an increase in the frequency of methylation of 12 CpG sites in exon 1A. Chromatin immunoprecipitation assays showed an increase in histone H3 methylation in cell lines without HSulf-1 expression. To assess the significance of HSulf-1 downregulation in ovarian cancer, OV167 and OV202 cells were transfected with HSulf-1 siRNA. Downregulation of HSulf-1 expression in OV167 and OV202 cells lead to an attenuation of cisplatin-induced cytotoxicity. Moreover, patients with ovarian tumors expressing higher levels of HSulf-1 showed a 90% response rate (27/30) to chemotherapy compared to a response rate of 63% (19/30) in those with weak or moderate levels (P ¼ 0.0146, v 2 test). Collectively, these data indicate that HSulf-1 is epigenetically silenced in ovarian cancer and that epigenetic therapy targeting HSulf-1 might sensitize ovarian tumors to conventional first-line therapies.

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The fundamental role of epigenetic events in cancer

Cited by 4,816 publications

References 91 publications

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

p21WAF1/CIP1 induction by 5-azacytosine nucleosides requires DNA damage

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

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