TSA-induced DNMT1 down-regulation represses hTERT expression via recruiting CTCF into demethylated core promoter region of hTERT in HCT116

Choi, Jee‐Hye; Min, Na Young; Park, Jina; Kim, Jin Hong; Park, Soo Hyun; Ko, Young Jin; Kang, Yejin; Moon, Young Joon; Rhee, Sangmyung; Ham, Seung Wook; Park, Ae Ja; Lee, Kwang-Ho

doi:10.1016/j.bbrc.2009.11.078

Cited by 53 publications

(49 citation statements)

References 28 publications

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“…Importantly, both sites showed a decreasing methylation pattern by inhibiting histone deacetylase by trichostatin A (data not shown) or DNA demethylation by homocysteine or 5-aza, which facilitated CTCF but interfered SP1 binding to the hTERT promoter but did not alter their expression. Surprisingly, different from Choi et al 11 and Meeran et al, 17 our ChIP analysis confirmed that homocysteine-or 5-azainduced demethylation promoted CTCF but prevented SP1 combining to the hTERT promoter. SP1 binding to homocysteine-induced unmethylated CpGs on the promoter of hTERT might be an activator for hTERT expression in normal ECs because siRNA knockdown of SP1 repressed hTERT expression and activity in ECs without but not with homocysteine treatment.…”

Section: Discussioncontrasting

confidence: 98%

“…9 Moreover, with the characterization of the genomic sequence of hTERT, demethylation with 5-aza-2-deoxycytodine (5-aza) or trichostatin A strongly reduced or even suppressed hTERT gene expression and telomerase activity and shortened telomere length in cancer cells. 10,11 Thus, epigenetic mediation of hTERT activity may be critical to carcinogenesis. Recently, our in vivo and in vitro experiments indicated that homocysteine could affect EC dysfunction and vascular smooth muscle cell migration or proliferation via an epigenetic mechanism involving 72 Arterioscler Thromb Vasc Biol January 2015…”

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confidence: 99%

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Homocysteine Accelerates Senescence of Endothelial Cells via DNA Hypomethylation of Human Telomerase Reverse Transcriptase

Zhang

Sun

Liu

et al. 2015

ATVB

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Objective-Homocysteine can accelerate the senescence of endothelial progenitor cells or endothelial cells (ECs) via telomerase inactivation and length shortening. However, the underlying mechanism is unclear. Here, we investigated whether homocysteine promotes endothelial senescence by reducing the expression and activity of human telomerase reverse transcriptase (hTERT) by DNA methylation to reduce ECs telomerase activity. Approach and Results-When compared with primary human umbilical vein endothelial cells grown under standard conditions, ECs with chronic homocysteine treatment showed accelerated upregulation of p16, p21, and p53, markers of cellular senescence, during 6 to 10 passages. Interestingly, homocysteine-stimulated but not angiotensin II-stimulated ECs senescence could be reversed by hypermethylation induced by folic acid or s-adenosylmethionine supplementation. Meanwhile, homocysteine promoted the shortening of telomere length specifically related to restoration of hTERT transcriptional expression and CCCTC-binding factor binding sites with hTERT promoter hypomethylation, as detected by quantitative real-time polymerase chain reaction, Western blot, methylation-specific polymerase chain reaction, and bisulfite sequencing assay. Electrophoretic mobility shift assay and chromatin immunoprecipitation results showed that homocysteine-reduced telomere activity and homocysteine-induced EC senescence might contribute to hTERT promoter demethylation by increasing CCCTC-binding factor repression and interfering in the SP1 binding to the demethylated hTERT promoter, which might relate with reduced of DNA methyltransferase 1. Furthermore, the CCCTC-binding factor-dependent mechanism of homocysteine-reduced hTERT expression via DNA demethylation was confirmed in aortic endothelia of mice with hyperhomocysteine levels. atherosclerosis-related genes. 6,12,13 Therefore, DNA demethylation of hTERT may be a candidate target of epigenetic regulation in homocysteine-induced EC senescence. However, homocysteine might reduce transcriptional hTERT expression by DNA hypomethylation, which reversed with homocysteine demethylation of soluble epoxide hydrolase or plateletderived growth factors and promoted their expression in our previous study. 12,13 This contradictory hypothesis prompted us to study how DNA methylation of the hTERT promoter can lead to its activation by homocysteine in ECs. Conclusions-CCCTC-bindingIn the core region of the 5′-hTERT promoter (−200 to +100 bp), several binding sites for activators (c-Myc, Sp1, AP2, E2F, and E-box) or repressors (p53, Mad1, MZF-2, ZRF, WT1, and CCCTC-binding factor [CTCF]) might be methylated and coregulate the expression of hTERT in human ECs. Zinn et al 14 demonstrated high expression of hTERT, despite DNA hypermethylation in several cancer cells, which contrasts with low expression with DNA hypomethylation in nontransformed cells, so some repressors might play a major role in hTERT expression and activity especially for DNA hypermethylation in some cancer cells. Similar...

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Section: Discussioncontrasting

confidence: 98%

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confidence: 99%

Homocysteine Accelerates Senescence of Endothelial Cells via DNA Hypomethylation of Human Telomerase Reverse Transcriptase

Zhang

Sun

Liu

et al. 2015

ATVB

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“…In the previous study, TSA repressed hTERT expression by recruiting CTCF into the demethylated core promoter region of hTERT by inducing DNMT1 down-regulation in HCT116 cells [Choi et al, 2010]. In our present study, the CTCF-binding site is partially methylated in untreated A549 cells.…”

Section: Discussionmentioning

confidence: 52%

“…In previously study, TSA, an inhibitor of HDAC, can down-regulation of DNMT1 and cause demethylation of a CTCF-binding site on the hTERT promoter. And TSA represses the expression of hTERT via recruitment of CTCF to the promoter [Choi et al, 2010].…”

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confidence: 99%

Vorinostat, SAHA, represses telomerase activity via epigenetic regulation of telomerase reverse transcriptase in non-small cell lung cancer cells

Hsiao

et al. 2011

J. Cell. Biochem.

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Vorinostat (suberoylanilide hydroxamic acid), a class of histone deacetylase inhibitors, represents an emerging class of anticancer agents currently progressing in clinical trials. It causes cell growth inhibition, differentiation, and apoptosis of many tumor types in vitro and in vivo. Recently, it was reported that hTERT is one of the targets for cancer therapy in cancer cells. Telomerase repeat amplification protocol assay was used to analyze the expression of hTERT after vorinostat treatment in the A549 lung cancer cells. Vorinostat inhibited telomerase activity by reducing the expression of human telomerase reverse transcriptase (hTERT) in A549 human lung cancer cells. The epigenetic regulation mechanism is responsible for the repression of hTERT by vorinostat, analyzed through the methylation-specific PCR and bisulfite sequencing of the hTERT promoter. Vorinostat induced the demethylation of site-specific CpGs on the promoter region of hTERT, which was caused by the down-regulation of DNA methyltransferases. DNA methyltransferases (DNMT1 and DNMT3b) were also decreased in vorinostat-treated A549 cancer cells. Furthermore, chromatin immunoprecipitation analysis of the hTERT promoter revealed that vorinostat decreased the level of inactive chromatin markers dimethyl-H3K9, and the declined binding of DNMT1 and DNMT3b were associated. The novel insights showed that vorinostat down-regulated telomerase via epigenetic alteration in lung cancer to vorinostat-mediated cancer-specific therapies.

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“…Finally, transcriptional repression of TERT is suggested to be due to the lack of CTCF-binding site on the promoter region, and such an example strengthens the regulatory role of epigenetic enzyme in telomerase expression of HCT116 cancer cell line. 81 The use of drug the 5-Aza-2′-deoxycytidine (5azadC) as an inhibitor of DNMT is widely documented, and findings support that taxol can be combined with 5azadC as a better therapeutic option for glioma to possibly target the TERT expression and activity. 82 In support of inhibitors targeted to epigenetic players as HDAC, the authors suggest the use of vorinostat (suberoylanilide hydroxamic acid), a class of HDACis capable of reducing the expression of telomerase in A549 human lung cancer cells.…”

Section: Epigenetic Inhibitors To Telomerase Therapeutic Quenchingmentioning

confidence: 99%

Epigenetic perturbation driving asleep telomerase reverse transcriptase: Possible therapeutic avenues in carcinoma

et al. 2017

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In the last decade, implications of human telomerase reverse transcriptase (hTERT), a component of ribonucleoprotein telomerase in aging, senescence, and stem cell are highly evident. Besides, the activation of hTERT is also being documented several cancer types including carcinoma. The awakening of telomerase during carcinoma initiation and development is being seen with different perspectives including genetic and epigenetic tools and events. In view of several tumor progenitors genes (also referred as epigenetic mediators), telomerase is placed as key enzyme to achieve the carcinoma phenotype and sustain during the progression. It is true that swaying of telomerase in carcinoma could be facilitated with dedicated set of epigenetic modulators and modifiers players. These epigenetic alterations are heritable, potentially reversible, and seen as the epigenetic signature of carcinoma. Several papers converge to suggest that DNA methylation, histone modification, and small non-coding RNAs are the widely appreciated epigenetic changes towards hTERT modulation. In this review, we summarize the contribution of epigenetic factors in the telomerase activation and discuss potential avenues to achieve therapeutic intervention in carcinoma.

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TSA-induced DNMT1 down-regulation represses hTERT expression via recruiting CTCF into demethylated core promoter region of hTERT in HCT116

Cited by 53 publications

References 28 publications

Homocysteine Accelerates Senescence of Endothelial Cells via DNA Hypomethylation of Human Telomerase Reverse Transcriptase

Homocysteine Accelerates Senescence of Endothelial Cells via DNA Hypomethylation of Human Telomerase Reverse Transcriptase

Vorinostat, SAHA, represses telomerase activity via epigenetic regulation of telomerase reverse transcriptase in non-small cell lung cancer cells

Epigenetic perturbation driving asleep telomerase reverse transcriptase: Possible therapeutic avenues in carcinoma

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