DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci

Rountree, Michael R.; Bachman, Kurtis E.; Baylin, Stephen B.

doi:10.1038/77023

Cited by 943 publications

(730 citation statements)

References 45 publications

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“…Epigenetic silencing can occur via promoter methylation and/or modification of histone tails in the chromatin. These two epigenetic events are closely linked and affect each other through the interaction of DNMT with the HDAC complex at methylated CpG sites (Robertson et al, 2000;Rountree et al, 2000). Pharmacologic (such as Aza treatment) or genetic demethylation (through double KO of DNMT1 and DNMT3B) results in the hypomethylation of genomic DNA, thus restoring the expression of methylation-silenced genes (Rhee et al, .…”

Section: Discussionmentioning

confidence: 99%

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Ying

Seng³

et al. 2005

Oncogene

245

288

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Protocadherins constitute the largest subgroup in the cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some are implicated in nervous system development. As tumorspecific promoter methylation is a marker for tumor suppressor genes (TSG), we searched for epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified the PCDH10 CpG island as a methylated sequence in nasopharyngeal carcinoma (NPC). PCDH10 is broadly expressed in all normal adult and fetal tissues including the epithelia, though at different levels. It resides at 4q28.3 -a region with hemizygous deletion detected by array-CGH in NPC cell lines; however, PCDH10 itself is not located within the deletion. In contrast, its transcriptional silencing and promoter methylation were frequently detected in multiple carcinoma cell lines in a biallelic way, including 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, 3/4 cervical, 2/5 lung and 2/8 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell line. Aberrant methylation was further frequently detected in multiple primary carcinomas (82% in NPC, 42-51% for other carcinomas), but not normal tissues. The transcriptional silencing of PCDH10 could be reversed by pharmacologic demethylation with 5-aza-2 0 -deoxycytidine or genetic demethylation with double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Ectopic expression of PCDH10 strongly suppressed tumor cell growth, migration, invasion and colony formation. Although the epigenetic and genetic disruptions of several classical cadherins as TSGs have been well documented in tumors, this is the first report that a widely expressed protocadherin can also function as a TSG that is frequently inactivated epigenetically in multiple carcinomas.

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Section: Discussionmentioning

confidence: 99%

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Ying

Seng³

et al. 2005

Oncogene

245

288

View full text Add to dashboard Cite

show abstract

“…These results imply that the action of 5Aza-dC is separate from the induction of promoter demethylation. It is possible that 5Aza-dC disrupts complexes between DNA methyltransferases and histone-modifying proteins [18,19]. Kondo et al [20] have reported that 5Aza-dC dramatically decreases histone H3 Lys-9 methylation, slightly increases Lys-9 acetylation, and moderately increases histone H3 Lys-4 methylation and reactivated gene expression.…”

Section: Discussionmentioning

confidence: 99%

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Murakami¹,

Asaumi²,

Maki³

et al. 2004

Oral Oncology

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Summary Maspin, which belongs to the serine protease inhibitor (serpin) superfamily, has been proposed as a potent tumor suppressor that inhibits cell motility, invasion, angiogenesis, and metastasis. In the present study, we examined the effects of 5-Aza-2'-deoxycytidine (5-Aza-dC), a demethylating agent, and FR901228, a histone deacetylase (HDAC) inhibitor, on maspin expression in oral cancer cell lines. The expression levels of maspin mRNA were divided into two groups, which was the maspin low-expressed and high-expressed cell lines in the 12 oral cancer cell lines. The maspin promoter contained only a few methylated CpG sites in the maspin low-expressed cell lines. Moreover, the methylation status was not altered after 5Aza-dC treatment. However, the transcription of the maspin gene was clearly increased following 5Aza-dC treatment in a number of oral cancer cell lines. These results imply that an action of 5Aza-dC is separate from induction of promoter demethylation. Treatment with FR901228 resulted in a time-dependent stimulation of the re-expression of maspin mRNA as early as 4 hours after treatment in the maspin downregulated cells. The re-expression of the maspin gene may contribute to the recuperation of biological functions linked to FR901228 such as an inhibitory effect on tumor angiogenesis and cell invasion. These results indicate that maspin and its target genes may be excellent leads for future studies on the potential benefits of FR901228, a histone deacetylase inhibitor, in cancer therapy.

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“…DNMT1 is the most abundant form of DNMTs in mammalian cells. DNMT1 functions primarily in maintenance methylation during DNA replication using hemimethylated DNA as substrates (Lyko et al, 1999;Robertson et al, 1999;Rountee et al, 2000;Robert et al, 2003;Suzuki et al, 2004). The reactions of de novo methylation using unmethylated DNA are thought to be primarily catalysed by DNMT3A and DNMT3B in mammals during early development (Okano et al, 1999;Bachman et al, 2001;Brueckner and Lyko, 2004;Hermann et al, 2004;Dodge et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Cigarette smoke induces demethylation of prometastatic oncogene synuclein-γ in lung cancer cells by downregulation of DNMT3B

et al. 2007

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The prometastatic oncogene synuclein-c (SNCG) is not expressed in normal lung tissues, but it is highly expressed in lung tumors. Here, we show that cigarette smoke extract (CSE) has strong inducing effects on SNCG gene expression in A549 lung cancer cells through demethylation of SNCG CpG island. CSE treatment also augments the invasive capacity of A549 cells in an SNCG-dependent manner. To elucidate the mechanisms underlying the demethylating effects of CSE, we examined expression levels of DNA methyltransferases (DNMTs), 1, 3A and 3B in CSE-treated cells. We show that the mRNA expression of DNMT3B is specifically downregulated by CSE with a kinetics concurrent to SNCG reexpression. Utilizing siRNA to knockdown DNMT3B expression, we show that inhibition of DNMT3B directly increases SNCG mRNA expression. We further show that exogenous overexpression of DNMT3B in an SNCG-positive lung cancer cell line H292 suppresses SNCG mRNA and protein expression and induces de novo methylation of SNCG CpG island, whereas overexpression of DNMT1 or DNMT3A has no effects. Taken together, these new findings demonstrate that tobacco exposure induces the abnormal expression of SNCG in lung cancer cells through downregulation of DNMT3B. This work sheds light on the molecular understanding of demethylation of this oncogene during cancer progression.

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DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci

Cited by 943 publications

References 45 publications

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

Cigarette smoke induces demethylation of prometastatic oncogene synuclein-γ in lung cancer cells by downregulation of DNMT3B

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