Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the
            <i>telomerase reverse transcriptase</i>
            promoter during differentiation of HL60 cells

Xu, Dawei; Popov, Nikita; Hou, Mi; Wang, Qian; Björkholm, Magnus; Gruber, Astrid; Menkel, Annette R.; Henriksson, Marie Arsenian

doi:10.1073/pnas.071043198

Cited by 273 publications

(292 citation statements)

References 41 publications

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“…Such transcription factors, for example Mad1 and MT-box-binding factor, have been reported to function as repressors of the hTERT promoter that act when cancer cell differentiation is induced by antagonizing the transcriptional activation ability of c-Myc (Tzukerman et al, 2000;Xu et al, 2001;Horikawa et al, 2002). Although our results showed that TAK1 represses the hTERT promoter activity in an E-box-independent manner, we cannot exclude the possibility that TAK1 represses the hTERT promoter even in an E-box-dependent manner.…”

Section: Discussioncontrasting

confidence: 63%

“…The E-box elements located in the core promoter region and the transcription factors that bind to it have been specifically focused upon. Several reports have demonstrated the critical role of c-Myc and its network proteins in regulating the hTERT promoter (Xu et al, 2001;Ducrest et al, 2002) and suggested that the ability of c-Myc to activate hTERT expression is one mechanism by which c-Myc exhibits its critical role. A large number of studies have reported the activation mechanisms of the hTERT promoter, whereas only a few studies have reported the repression mechanisms of the hTERT promoter (Ducrest et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Several proteins were reported to repress the hTERT promoter activity by binding to Sp1 (Ducrest et al, 2002). Further, the Sp1 family proteins associate with the hTERT promoter, recruiting HDAC for histone deacetylation and transcriptional silencing of the hTERT gene in normal human somatic cells (Cong and Bacchetti, 2000;Takakura et al, 2001;Xu et al, 2001;Hou et al, 2002;Won et al, 2002). We then investigated the possible involvement of the Sp1 family proteins and HDAC in the TAK1-induced hTERT gene repression.…”

Section: Tak1 Represses Htert Transcription T Fujiki Et Almentioning

confidence: 99%

“…Recently, several researchers have proposed mechanisms of transcriptional silencing of the hTERT gene in normal cells. Experiments on a wide variety of normal human somatic cells with trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), suggest that histone deacetylation is essential to the transcriptional silencing of the hTERT gene (Cong and Bacchetti, 2000;Takakura et al, 2001;Xu et al, 2001) and that Sp1 and Sp3 associate with the hTERT promoter, recruiting HDAC for localized histone deacetylation (Hou et al, 2002;Won et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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TAK1 represses transcription of the human telomerase reverse transcriptase gene

et al. 2007

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In human cells, telomerase activity is tightly regulated by the expression of its catalytic subunit, namely, the human telomerase reverse transcriptase (hTERT). However, the molecular mechanisms involved in the regulation of hTERT expression have not been completely clarified. We have previously reported that transforming growth factor b (TGF-b) represses the expression of the hTERT gene. In the present study, we demonstrated that TGF-bactivated kinase 1 (TAK1), originally identified as a mitogen-activated kinase kinase kinase, represses the hTERT core promoter activity in an E-box-independent manner, and it also represses the transcription of the hTERT gene in human lung adenocarcinoma cell line, A549 cells. This TAK1-induced repression was found to be caused by the recruitment of histone deacetylase to Sp1 at the hTERT promoter and a consequent reduction in the amount of acetylated histone H4 at the hTERT promoter. Finally, we demonstrated that TAK1 induces cellular senescence programs in normal human diploid cells. Thus, we assume that TAK1 triggers the repression mechanisms of the hTERT gene as a result of evoking cellular senescence programs. Considered together, TAK1 is thought to play a causative role in the determination of a finite replicative lifespan of normal and cancer cells.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Tak1 Represses Htert Transcription T Fujiki Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TAK1 represses transcription of the human telomerase reverse transcriptase gene

et al. 2007

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“…The hTERT gene is likely to be targeted by epigenetic regulation such as histone acetylation or promoter methylation. Some reports showed that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) could activate hTERT expression in telomerase-negative cells [6,7,31,37]. Hou et al reported that TSA and the protein synthesis inhibitor cycloheximide (CHX) induced hTERT mRNA [13], suggesting that this induction does not require de novo protein synthesis and is likely a direct result of HDAC inhibition at the hTERT gene.…”

Section: Introductionmentioning

confidence: 99%

Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer

Murakami

Asaumi

Kawai

et al. 2005

Cancer Chemother Pharmacol

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We speculated whether or not the expression level of telomerase reverse transcriptase (hTERT) would be modulated by agents targeting epigenetics in oral cancer cell lines. Although hTERT is known to be targeted by epigenetic changes, it remains unclear how chemoagents targeting epigenetics work on hTERT transcription. In the present study, the epigenetic effects of histone deacetylase (HDAC) inhibitor FR901228 on hTERT transcription were analysed by RT-PCR in oral cancer cell lines. The mRNA expression of hTERT was upregulated after exposure to FR901228 in hTERT-negative Hep2 cells, even in the hTERT highly expressed SAS and KB cells.Moreover, co-treatment of protein synthesis inhibitor cycloheximide (CHX) resulted in the induction of hTERT transcription by FR901228. This suggests that the induction of hTERT by FR901228 requires de novo protein synthesis to some extent and is more likely a direct than an indirect effect on epigenetic changes such as histone acetylation / deacetylation. We further examined the effect of FR901228 on c-myc protein, which is one of the main hTERT transcription activators. FR901228 repressed c-myc protein only in the absence of CHX, dependent of the enhancement of de novo protein synthesis. Our results indicate that c-myc protein is repressed indirectly by FR901228 but may not contribute FR901228-induced hTERT transcription. The present study showed that the HDAC inhibitor FR901228 induced the hTERT gene by a complex mechanism that involved other transcription factors except for c-myc, in addition to the inhibition of histone deacetylation.

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Allele‐specific proximal promoter hypomethylation of the telomerase reverse transcriptase gene (TERT) associates with TERT expression in multiple cancers

2020

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Telomerase reverse transcriptase (TERT) is pathologically expressed in the vast majority of human cancers, but the epigenetic regulation of its expression is only beginning to be understood. In particular, the active TERT gene in cancer cells has been characterized as having a hypermethylated CpG island, opposite to the general association of DNA methylation with gene repression. Here, we analyzed TERT promoter CpG methylation in 833 human cancer cell lines representing 23 different tissue types and found hypermethylation of the upstream portion of the CpG island and more conserved hypomethylation of a region including the proximal TERT promoter and exon 1. In cell lines with monoallelic expression of TERT, we found allelic methylation of the proximal TERT promoter. This included cell lines with the À124 or À146 activating promoter mutation as well as wild-type TERT cancer lines. In these cell line types, decreased proximal promoter methylation is associated with the active allele. Compared to cells with monoallelic expression of TERT, lines with biallelic expression of TERT had even lower methylation in the proximal TERT promoter. Thus, in cell lines from cancers of many different tissues, the TERT proximal promoter has canonical DNA methylation, with low methylation correlating with increased TERT expression.

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Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells

Cited by 273 publications

References 41 publications

TAK1 represses transcription of the human telomerase reverse transcriptase gene

TAK1 represses transcription of the human telomerase reverse transcriptase gene

Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer

Allele‐specific proximal promoter hypomethylation of the telomerase reverse transcriptase gene (TERT) associates with TERT expression in multiple cancers

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