Human telomerase reverse transcriptase (hTERT) is a target gene of β-catenin in human colorectal tumors

Jaitner, Stefanie; Reiche, Jana A; Schäffauer, A.J.; Hiendlmeyer, Elke; Herbst, Hermann; Brabletz, Thomas; Kirchner, Thomas; Jung, Andreas

doi:10.4161/cc.21790

Cited by 31 publications

(24 citation statements)

References 39 publications

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“…Recent reports identified a direct link between the Wnt/β-catenin signaling pathway and hTERT expression in normal embryonic and adult stem cells and cancer cells [42], [43], [44]. Interestingly, our data demonstrate that there is a context-dependent regulation of the hTERT promoter by the HH/GLI signaling pathway.…”

Section: Discussionsupporting

confidence: 58%

Hedgehog Signaling Regulates Telomerase Reverse Transcriptase in Human Cancer Cells

et al. 2013

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The Hedgehog (HH) signaling pathway is critical for normal embryonic development, tissue patterning and cell differentiation. Aberrant HH signaling is involved in multiple human cancers. HH signaling involves a multi-protein cascade activating the GLI proteins that transcriptionally regulate HH target genes. We have previously reported that HH signaling is essential for human colon cancer cell survival and inhibition of this signal induces DNA damage and extensive cell death. Here we report that the HH/GLI axis regulates human telomerase reverse transcriptase (hTERT), which determines the replication potential of cancer cells. Suppression of GLI1/GLI2 functions by a C-terminus truncated GLI3 repressor mutant (GLI3R), or by GANT61, a pharmacological inhibitor of GLI1/GLI2, reduced hTERT protein expression in human colon cancer, prostate cancer and Glioblastoma multiforme (GBM) cell lines. Expression of an N-terminus deleted constitutively active mutant of GLI2 (GLI2ΔN) increased hTERT mRNA and protein expression and hTERT promoter driven luciferase activity in human colon cancer cells while GANT61 inhibited hTERT mRNA expression and hTERT promoter driven luciferase activity. Chromatin immunoprecipitation with GLI1 or GLI2 antibodies precipitated fragments of the hTERT promoter in human colon cancer cells, which was reduced upon exposure to GANT61. In contrast, expression of GLI1 or GLI2ΔN in non-malignant 293T cells failed to alter the levels of hTERT mRNA and protein, or hTERT promoter driven luciferase activity. Further, expression of GLI2ΔN increased the telomerase enzyme activity, which was reduced by GANT61 administration in human colon cancer, prostate cancer, and GBM cells. These results identify hTERT as a direct target of the HH signaling pathway, and reveal a previously unknown role of the HH/GLI axis in regulating the replication potential of cancer cells. These findings are of significance in understanding the important regulatory mechanisms that determine the functions of HH/GLI signaling in cancer cells.

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Section: Discussionsupporting

confidence: 58%

Hedgehog Signaling Regulates Telomerase Reverse Transcriptase in Human Cancer Cells

et al. 2013

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“…Therefore whole RNA was isolated from microdissected tumor areas using RNeasy kits (Qiagen; 74404) as previously described [24]. RNA concentrations were measured by UV-photometry.…”

Section: Methodsmentioning

confidence: 99%

Microsatellite Instability, KRAS Mutations and Cellular Distribution of TRAIL-Receptors in Early Stage Colorectal Cancer

et al. 2012

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BackgroundThe fact that the receptors for the TNF-related apoptosis inducing ligand (TRAIL) are almost invariably expressed in colorectal cancer (CRC) represents the rationale for the employment of TRAIL-receptors targeting compounds for the therapy of patients affected by this tumor. Yet, first reports on the use of these bioactive agents provided disappointing results. We therefore hypothesized that loss of membrane-bound TRAIL-R might be a feature of some CRC and that the evaluation of membrane staining rather than that of the overall expression of TRAIL-R might predict the response to TRAIL-R targeting compounds in this tumor.Aim and MethodsThus, we evaluated the immunofluorescence pattern of TRAIL-receptors and E-cadherin to assess the fraction of membrane-bound TRAIL-receptors in 231 selected patients with early-stage CRC undergoing surgical treatment only. Moreover, we investigated whether membrane staining for TRAIL-receptors as well as the presence of KRAS mutations or of microsatellite instability (MSI) had an effect on survival and thus a prognostic effect.ResultsAs expected, almost all CRC samples stained positive for TRAIL-R1 and 2. Instead, membrane staining for these receptors was positive in only 71% and 16% of samples respectively. No correlation between KRAS mutation status or MSI-phenotype and prognosis could be detected. TRAIL-R1 staining intensity correlated with survival in univariate analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on cell membranes was an independent predictor of survival (cox multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12–3.77]; TRAIL-R2: p = 0.033, RR 3.63[1.11–11.84]).ConclusionsIn contrast to the current assumptions, loss of membrane staining for TRAIL-receptors is a common feature of early stage CRC which supersedes the prognostic significance of their staining intensity. Failure to achieve therapeutic effects in recent clinical trials using TRAIL-receptors targeting compounds might be due to insufficient selection of patients bearing tumors with membrane-bound TRAIL-receptors.

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“…Several studies concluded that telomerase played a key role in regulating cell proliferation which is associated with various disorders (e.g. endometriosis and colorectal cancer) [29][30][31][32]. In fact, Wnt/β-catenin has been documented to exacerbate cell proliferation by binding with the T-cell factor (TCF)/ lymphoid-enhancing factor (LEF) family and inducing some oncogene expressions including C-myc and cyclin D1(CCND1) [33].…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-Catenin Signaling Exacerbates Keloid Cell Proliferation by Regulating Telomerase

Shang

Yuan

et al. 2016

Cell Physiol Biochem

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Objectives: Our goal was to investigate the relationship between keloid and telomerase as well as clarifying the influence of Wnt/β-catenin signaling on keloid cell proliferation. Methods: Tissues from 18 keloid patients were collected for further study. Keloid progenitor cells (KPC) and skin progenitor cells (SKP) were both included in this study. Lenti-virus transfection was used to divide cells into different groups in which cells were treated with different substances: negative control (NC) group, wnt10a siRNA group, β-catenin siRNA group and TERT siRNA group. KPC cells were injected into 20 male BALB/c nude mice in order to build tumor models. Several experiments including immunohistochemistry, western blot and RT-PCR were conducted in order to detect the corresponding protein expressions and relative mRNA levels. MTT assay and flow cytometry were also conducted for assessing cell proliferation and apoptosis status. Results: β-catenin and telomerase expression levels in keloid tissues were elevated compared to normal tissues (all P < 0.05). KPC cells in keloid exhibited more dynamic telomerase activity than SKP cells (P < 0.05). Luciferase activity assay confirmed that β-catenin could directly interact with telomerase. After wnt10a/β-catenin signaling pathway was inhibited, the proliferation of KPC cells was significantly suppressed and the apoptosis rate was remarkably increased (all P < 0.05). Results from tumor models also validated that wnt10a/β-catenin signaling pathway influenced the activity and length of telomerase. Conclusions: Wnt/β-catenin signaling pathway is able to exacerbate keloid cell proliferation and inhibit the apoptosis of keloid cells through its interaction with telomerase.

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Human telomerase reverse transcriptase (hTERT) is a target gene of β-catenin in human colorectal tumors

Abstract: (2012) Human telomerase reverse transcriptase (hTERT) is a target gene of β-catenin in human colorectal tumors, Cell Cycle, 11:17,[3331][3332][3333][3334][3335][3336][3337][3338]

Cited by 31 publications

References 39 publications

Hedgehog Signaling Regulates Telomerase Reverse Transcriptase in Human Cancer Cells

Hedgehog Signaling Regulates Telomerase Reverse Transcriptase in Human Cancer Cells

Microsatellite Instability, KRAS Mutations and Cellular Distribution of TRAIL-Receptors in Early Stage Colorectal Cancer

Wnt/β-Catenin Signaling Exacerbates Keloid Cell Proliferation by Regulating Telomerase

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