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Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer

ABSTRACT: Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer

PROVIDER: PRJNA684614 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13243045_1.fastq.gz	Fastqsanger.gz
	SRR13243045_2.fastq.gz	Fastqsanger.gz
	SRR13243046_1.fastq.gz	Fastqsanger.gz
	SRR13243046_2.fastq.gz	Fastqsanger.gz
	SRR13243047_1.fastq.gz	Fastqsanger.gz

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HoxC5 and Pbx4 repress hTERT to limit telomerase activity

Project description:Telomere elongation by telomerase is critical for the proliferation of human stem cells and >85-90% of cancer cells. The repression of telomerase activity during cellular differentiation promotes replicative aging and function as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain unclear. We found that HoxC5 repressed hTERT, via a previously uncharacterized upstream enhancer element. HoxC5 interacts with co-repressors Pbx4 and Meis3, and recruits Class I histone deacetylases, to mediate repression of hTERT. The upstream enhancer element are conserved in long-lived primates, and HOXC5 are activated upon differentiation, consistent with diminished telomerase activity. Thus, HoxC5/Pbx4/Meis3 together constitute a developmental-controlled regulatory loop that coordinates transcriptional repression of hTERT.

2018-02-13 | GSE97570 | GEO

Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer.

Project description:Transcriptional reactivation of hTERT is the limiting step in tumorigenesis. While mutations in hTERT promoter present in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, remain unknown. Using primary colorectal cancers (CRC) we identified Tert INTeracting region 2 (T-INT2), the critical chromatin region essential for reactivating WT-hTERT promoter in CRCs. Elevated β-catenin and JunD level in CRC facilitates chromatin interaction between hTERT promoter and T-INT2 that is necessary to turn on hTERTexpression. Pharmacological screens uncovered salinomycin, which inhibits JunD mediated hTERT-T-INT2 interaction that is required for the formation of a stable transcription complex on the hTERT promoter. Our results showed for the first time how known CRC alterations, such as APC, lead to WT-hTERT promoter reactivation during stepwise-tumorigenesis and provide a new perspective for developing cancer-specific drugs.

| S-EPMC9841410 | biostudies-literature

GSK3 activates telomerase by regulating dynamic behaviour of multiple transcription factors converging on the hTERT gene

Project description:Telomerase controls cell immortality and is a promising cancer target. Understanding transcriptional regulation of the catalytic subunit hTERT is critical to realise effective telomerase therapeutics. GSK3 inhibition suppresses hTERT expression.

2009-08-03 | GSE14532 | GEO

Identification of mechanism of cancer-cell-specific reactivation of hTERT offers therapeutic opportunities for blocking telomerase specifically in human colorectal cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-01-08 | GSE163077 | GEO

Mutated RNA component of the telomerase induces apoptosis via GADD45-? in hTERT-overexpressing primary fibroblasts

Project description:Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancerous cells that have high telomerase activity. However, the exact mechanisms by which MT-hTers inhibit the growth of cancer cells and affect normal somatic cells remain largely unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 primary lung fibroblasts that have very low endogenous hTERT levels. Growth of IMR90 cells following MT-hTers infection was not impaired, however, cell proliferation of IMR90 wild-type hTERT (WT-hTERT) cells under MT-hTers-47A and -AU5 treatment was inhibited and increased cell death was observed. FACS analysis also showed that these cells underwent apoptosis. Confocal microscopy revealed that MT-hTers induced DNA damage foci, i.e., 53BP1 and ?-H2AX, in immortalized IMR90 WT-hTERT cells. Microarray analysis of the IMR90 WT-hTERT MT-hTer-47A and -AU5 versus IMR90 MT-hTer-47A and -AU5 revealed that GADD45-? was significantly elevated, and this result was further confirmed following RT-PCR and real time PCR assays. Moreover, we have showed that MT-hTers induce ATM phosphorylation at Ser 1981 in IMR90 WThTERT cells, and Western analysis revealed high levels of phospho p53 expression in these cells following activation of ATM. Our results also suggest that p53-dependent apoptosis in MT-hTers-infected IMR90 WT-hTERT cells could be due to a decreased expression of TRF2. Taken together, we propose a model that MT-hTers induce DSBs-like damages and trigger programmed cell death in IMR90 WT-hTERT cells following ATM-mediated phosphorylation of p53, which in turn upregulate GADD45-?, ultimately leading to apoptosis. MT-hTer-47A and -AU5 were introduced into IMR90 primary lung fibroblasts and immortalized IMR90 WT-hTERT cells. Through microarray analysis, gene expression of MT-hTer-infected IMR90 WT-hTERT cells were compared against MT-hTer-infected IMR90 control cells.

2011-05-28 | E-GEOD-24975 | biostudies-arrayexpress

Mass spectrum for identifying the interacting proteins of telomerase reverse transcriptase

Project description:The 293T cells overexpressing human telomerase reverse transcriptase (hTERT) were lysed and co-immunoprecipitation was performed using hTERT antibody. Then protein mass spectrum was conducted in order to identify the hTERT-interacting proteins.

2024-01-26 | PXD048859 | Pride

Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

Project description:To investigate the mechanism of telomerase regulation in BCR-ABL positive cells due to its clinical value, we studied the catalytic component of telomerase, TERT. Our results suggest that BCR-ABL plays an important role in regulating hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was downregulated, therefore suggesting a positive correlation between BCR-ABL and hTERT. Gleevec treatment inhibited hTERT at the mRNA level and significantly reduced telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells. TRAP assay also revealed that Gleevec treatment significantly reduced TA specifically in K562 cells. Furthermore, translocation of hTERT from nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec. Although Gleevec down-regulated hTERT mRNA level, the protein level of hTERT remained unchanged. Therefore, Gleevec-induced-TA decrease is not due to the alteration in telomerase subunits expression. It could be presumably due to posttranslational modification of hTERT, possibly through multiple signaling pathways. We have found that Gleevec reduced the tyrosine phosphorylation of hTERT by BCR-ABL, which is associated with the nucleoplasm localization of hTERT from nucleoli sequesters. These findings reveal unknown functions and regulations of telomerase by BCR-ABL.

2011-12-15 | GSE26821 | GEO

Alternative splicing is a developmental switch for hTERT expression

Project description:Telomere length control is critical for cellular lifespan and tumor suppression. Telomerase is activated in the inner cell mass of the developing blastocyst to reset telomere reserves and its subsequent silencing in differentiated cells leads to gradual telomere shortening. Here, we report that transcriptional control through cis-regulatory elements minimally impact telomerase regulation as a function of pluripotency. Instead, developmental control of telomerase is largely driven by an alternative splicing event, centered around hTERT exon-2. Skipping of exon-2 triggers hTERT mRNA decay in differentiated cells. Conversely, its retention in pluripotent cells promotes telomerase accumulation. Our study also identifies SON as a regulator of exon-2 alternative splicing and we report a patient with insufficient telomerase and short telomeres and harboring a SON mutation. In summary, our study highlights a critical role for hTERT alternative splicing in the developmental regulation of telomerase and implicates defective splicing in telomere biology disorders.

2021-03-04 | GSE168193 | GEO

Regulation of hTERT by BCR-ABL at multiple levels in K562 cells

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Chemical genomic screen identifies SP2509, WT hTERT specific repressor in colorectal cancer

Project description:Telomerase is necessary for cell immortality in cancer. Hence, during tumerognesis cancer cells reactivates telomerase to attain uncotrolled proliferation. There are no clinically approved drugs available to inhibit telomerase in cancer. We performed a chemical screen using a novel endogenous hTERT reported cell line and identified a compound, SP2509 which acts specifically in cancer cells immortalised by WT TERT activity. Further we identified that Pirin is a molecular target of the compund and it regulate the level of SP1, an important transcriptional activator of WT TERT gene. We finally show iron dependency of pirin to activate TERT in CRC cell lines.

2022-12-01 | GSE203120 | GEO

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