scholarly journals Telomerase Regulation: A Role for Epigenetics

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1213
Author(s):  
Fatma Dogan ◽  
Nicholas R. Forsyth
Keyword(s):  
Cellular Transformation ◽  
Telomerase Activity ◽  
Limiting Factor ◽  
Systematic Analysis ◽  
Diagnosis And Prognosis ◽  
Development And Differentiation ◽  
Telomere Biology ◽  
Promoter Mutations ◽  
Telomerase Regulation

Telomerase was first described by Greider and Blackburn in 1984, a discovery ultimately recognized by the Nobel Prize committee in 2009. The three decades following on from its discovery have been accompanied by an increased understanding of the fundamental mechanisms of telomerase activity, and its role in telomere biology. Telomerase has a clearly defined role in telomere length maintenance and an established influence on DNA replication, differentiation, survival, development, apoptosis, tumorigenesis, and a further role in therapeutic resistance in human stem and cancer cells including those of breast and cervical origin. TERT encodes the catalytic subunit and rate-limiting factor for telomerase enzyme activity. The mechanisms of activation or silencing of TERT remain open to debate across somatic, cancer, and stem cells. Promoter mutations upstream of TERT may promote dysregulated telomerase activation in tumour cells but additional factors including epigenetic, transcriptional and posttranscriptional modifications also have a role to play. Previous systematic analysis indicated methylation and mutation of the TERT promoter in 53% and 31%, respectively, of TERT expressing cancer cell lines supporting the concept of a key role for epigenetic alteration associated with TERT dysregulation and cellular transformation. Epigenetic regulators including DNA methylation, histone modification, and non-coding RNAs are now emerging as drivers in the regulation of telomeres and telomerase activity. Epigenetic regulation may be responsible for reversible silencing of TERT in several biological processes including development and differentiation, and increased TERT expression in cancers. Understanding the epigenetic mechanisms behind telomerase regulation holds important prospects for cancer treatment, diagnosis and prognosis. This review will focus on the role of epigenetics in telomerase regulation.

scholarly journals Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

2019 ◽  
Vol 20 (6) ◽  
pp. 1333 ◽  
Author(s):  
Alessandra Ventura ◽  
Cristina Pellegrini ◽  
Ludovica Cardelli ◽  
Tea Rocco ◽  
Valeria Ciciarelli ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Telomerase Activity ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Telomere Biology ◽  
Promoter Mutations

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.

Telomeres: the role of shortening and senescence in major depressive disorder and its therapeutic implications

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Jessica Daniela Schroder ◽  
Julia Beatrice de Araújo ◽  
Tacio de Oliveira ◽  
Airam Barbosa de Moura ◽  
Gabriel Rodrigo Fries ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Telomerase Activity ◽  
Biological Aging ◽  
Biological Mechanisms ◽  
Major Depressive ◽  
Number Of Patients ◽  
Telomere Biology

Abstract Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitro protocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.

InTERTesting association between telomerase, mTOR and phytochemicals

2012 ◽  
Vol 14 ◽  
Author(s):  
Tabetha Sundin ◽  
Patricia Hentosh
Keyword(s):  
Dna Sequences ◽  
Mammalian Target Of Rapamycin ◽  
Heat Shock Protein 90 ◽  
Protein Translation ◽  
Telomerase Activity ◽  
Gene Coding ◽  
Functional Complex ◽  
Telomerase Regulation ◽  
Rate Limiting

Telomeres are stretches of repeated DNA sequences located at the ends of chromosomes that are necessary to prevent loss of gene-coding DNA regions during replication. Telomerase – the enzyme responsible for immortalising cancer cells through the addition of telomeric repeats – is active in ~90% of human cancers. Telomerase activity is inhibited by various phytochemicals such as isoprenoids, genistein, curcumin, epigallocatechin-3-gallate, resveratrol and others. Human TERT (telomerase reverse transcriptase – the rate-limiting component of telomerase), heat shock protein 90, Akt, p70 S6 kinase (S6K) and mammalian target of rapamycin (mTOR) form a physical and functional complex with one another. The inclusion of Akt, mTOR and S6K in the TERT complex is compelling evidence to support mTOR-mediated control of telomerase activity. This review will define the role of mTOR, the master regulator of protein translation, in telomerase regulation and provide additional insights into the numerous ways in which telomerase activity is hindered by phytochemicals.

scholarly journals Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1624
Author(s):  
Marta Mellai ◽  
Omar Porrini Prandini ◽  
Aurora Mustaccia ◽  
Valentina Fogazzi ◽  
Marta Allesina ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Gene Promoter ◽  
Tumour Heterogeneity ◽  
Histologic Diagnosis ◽  
Diagnosis And Prognosis ◽  
Tert Gene ◽  
Tert Promoter Mutations ◽  
Benign Tumours ◽  
Promoter Mutations

Background: The role of telomerase reverse transcriptase (TERT) gene promoter mutations (pTERT) in atypical and anaplastic meningiomas remains controversial. This study aimed to evaluate their impact on the histologic diagnosis and prognosis in a retrospective series of 74 patients with atypical and anaplastic meningioma, including disease progression and relapse. A supplementary panel of 21 benign tumours was used as a control cohort. Materials and Methods: The mutation rate of the pTERT gene was assessed by Sanger sequencing. ATRX protein expression was detected by immunohistochemistry. The phenotypic and genotypic intra-tumour heterogeneity was studied in a sub-group of 12 cases using a Molecular Machines & Industries (MMI) CellCut laser microdissection (LMD) system. Results: pTERT mutations were detected in 12/74 (17.6%) malignant meningiomas. The mutation rate was significantly higher in anaplastic meningiomas (7/23, 30.4%) compared to atypical tumours (5/48, 10.4%) (p = 0.0443). In contrast, the mutation rate was < 5% in benign tumours. All pTERT mutant cases retained nuclear ATRX immunoreactivity. pTERT mutations were significantly associated with the histologic grade (p = 0.0443) and were adverse prognostic factors for anaplastic tumours (p = 0.06). Conclusion: We reported on the pTERT mutation spectrum in malignant meningiomas, supporting their use in the prognostic classification.

scholarly journals Telomerase and Telomeres Biology in Thyroid Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2887 ◽  
Author(s):  
Benedetta Donati ◽  
Alessia Ciarrocchi
Keyword(s):  
Current Knowledge ◽  
Telomerase Activity ◽  
High Rate ◽  
Cancer Therapies ◽  
Telomerase Inhibitors ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Telomere Regulation ◽  
Promoter Mutations

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.

scholarly journals Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3145
Author(s):  
Karolin Walter ◽  
Eva Rodriguez-Aznar ◽  
Monica S. Ventura Ferreira ◽  
Pierre-Olivier Frappart ◽  
Tabea Dittrich ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Pancreatic Cancer Cells ◽  
Sphere Formation ◽  
Telomerase Regulation ◽  
Pancreatic Cancer Stem Cells

To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.

scholarly journals TERT, a promoter of CNS malignancies

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Bhuvic Patel ◽  
Rukayat Taiwo ◽  
Albert H Kim ◽  
Gavin P Dunn
Keyword(s):  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Promoter Hypermethylation ◽  
Telomerase Activity ◽  
Cns Tumors ◽  
Replication Process ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Telomere Biology ◽  
Promoter Mutations

Abstract As cells replicate their DNA during mitosis, telomeres are shortened due to the inherent limitations of the DNA replication process. Maintenance of telomere length is critical for cancer cells to overcome cellular senescence induced by telomere shortening. Telomerase reverse transcriptase (TERT) is the rate-limiting catalytic subunit of telomerase, an RNA-dependent DNA polymerase that lengthens telomeric DNA to maintain telomere homeostasis. TERT promoter mutations, which result in the upregulation of TERT transcription, have been identified in several central nervous system (CNS) tumors, including meningiomas, medulloblastomas, and primary glial neoplasms. Furthermore, TERT promoter hypermethylation, which also results in increased TERT transcription, has been observed in ependymomas and pediatric brain tumors. The high frequency of TERT dysregulation observed in a variety of high-grade cancers makes telomerase activity an attractive target for developing novel therapeutics. In this review, we briefly discuss normal telomere biology, as well as the structure, function, and regulation of TERT in normal human cells. We also highlight the role of TERT in cancer biology, focusing on primary CNS tumors. Finally, we summarize the clinical significance of TERT promoter mutations in cancer, the molecular mechanisms through which these mutations promote oncogenesis, and recent advances in cancer therapies targeting TERT.

The miR-21 potential of serving as a biomarker for liver diseases in clinical practice

2020 ◽  
Vol 48 (5) ◽  
pp. 2295-2305
Author(s):  
Jiawei Zhang ◽  
Dandan Li ◽  
Rui Zhang ◽  
Peng Gao ◽  
Rongxue Peng ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Liver Diseases ◽  
Hepatic Disease ◽  
Noninvasive Detection ◽  
Diagnosis And Prognosis ◽  
Expected Performance ◽  
Potential Biomarker ◽  
Disease Condition ◽  
Complex Regulatory Network

The role of miR-21 in the pathogenesis of various liver diseases, together with the possibility of detecting microRNA in the circulation, makes miR-21 a potential biomarker for noninvasive detection. In this review, we summarize the potential utility of extracellular miR-21 in the clinical management of hepatic disease patients and compared it with the current clinical practice. MiR-21 shows screening and prognostic value for liver cancer. In liver cirrhosis, miR-21 may serve as a biomarker for the differentiating diagnosis and prognosis. MiR-21 is also a potential biomarker for the severity of hepatitis. We elucidate the disease condition under which miR-21 testing can reach the expected performance. Though miR-21 is a key regulator of liver diseases, microRNAs coordinate with each other in the complex regulatory network. As a result, the performance of miR-21 is better when combined with other microRNAs or classical biomarkers under certain clinical circumstances.

Testing ecological release as a compensating mechanism for mass mortality in a keystone predator

2020 ◽  
Vol 637 ◽  
pp. 59-69 ◽  
Author(s):  
J Sullivan-Stack ◽  
BA Menge
Keyword(s):  
Community Dynamics ◽  
Limiting Factor ◽  
Sea Star ◽  
Top Predator ◽  
Oregon Coast ◽  
Ecological Release ◽  
Keystone Predator ◽  
Pisaster Ochraceus ◽  
Wasting Syndrome

Top predator decline has been ubiquitous across systems over the past decades and centuries, and predicting changes in resultant community dynamics is a major challenge for ecologists and managers. Ecological release predicts that loss of a limiting factor, such as a dominant competitor or predator, can release a species from control, thus allowing increases in its size, density, and/or distribution. The 2014 sea star wasting syndrome (SSWS) outbreak decimated populations of the keystone predator Pisaster ochraceus along the Oregon coast, USA. This event provided an opportunity to test the predictions of ecological release across a broad spatial scale and determine the role of competitive dynamics in top predator recovery. We hypothesized that after P. ochraceus loss, populations of the subordinate sea star Leptasterias sp. would grow larger, more abundant, and move downshore. We based these predictions on prior research in Washington State showing that Leptasterias sp. competed with P. ochraceus for food. Further, we predicted that ecological release of Leptasterias sp. could provide a bottleneck to P. ochraceus recovery. Using field surveys, we found no clear change in density or distribution in Leptasterias sp. populations post-SSWS, and decreases in body size. In a field experiment, we found no evidence of competition between similar-sized Leptasterias sp. and P. ochraceus. Thus, the mechanisms underlying our predictions were not in effect along the Oregon coast, which we attribute to differences in habitat overlap and food availability between the 2 regions. Our results suggest that response to the loss of a dominant competitor can be unpredictable even when based in theory and previous research.

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