High incidence of TERT mutation in brain tumor cell lines

Johanns, Tanner M.; Fu, Yujie; Kobayashi, Dale K.; Yu, Mei; Dunn, Ian F.; Mao, Diane D.; Kim, Albert H.; Dunn, Gavin P.

doi:10.1007/s10014-016-0257-5

Cited by 27 publications

(27 citation statements)

References 25 publications

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“…While these are somatic mutations, a germline mutation at position −57A>C from the TSS has been identified in familial melanomas and showed similar effects [49]. All of these mutations have similar effects, increasing TERT expression~2-6 fold as measured through qRT-PCR, immunohistochemistry, TRAP, or reporter vectors in numerous cancer types, as outlined in Table 1 [37,50,[52][53][54][55][56][57][58][59][60][61][62][63][64][65]. This increased TERT expression maintains self-renewal potential and telomeres in both stem cells and terminally differentiated bladder cells, indicating that these mutations are sufficient to immortalize cells [66,67].…”

Section: Telomerase Reverse Transcriptase Promoter (Tertp) Mutationsmentioning

confidence: 95%

“…TERTp mutations have been recorded in a wide range of solid cancers. They are present in primary gliomas and glioblastoma multiforme (GBM), oligodendrogliomas and astrocytomas [10,40,[52][53][54]57,58,60,64,65,[77][78][79][80][81][82][83][84][85][86], melanomas, cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [49][50][51][52]55,[87][88][89][90][91], myxoid liposarcomas [77], urothelial bladder carcinoma [50,57,78,[92][93][94], hepatocellular carcinoma (HCC) [50,57,62,[95][96][97], and thyroid cancers [98][99][100][101][102]…”

Section: Telomerase Reverse Transcriptase Promoter (Tertp) Mutationsmentioning

confidence: 99%

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The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

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The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.Cells 2020, 9, 749 2 of 28 by copy number variants (CNV), TERT or TERTp structural variants, chromosomal rearrangements juxtaposing TERTp to enhancer elements, cellular and viral oncogenes such as Hepatitis B virus (HBV) X protein (HBx) or high-risk Human papillomavirus (HPV)16 and HPV18 E6 oncoprotein, and, last but not least, mutations within TERTp (31% of TERT-expressing cancers) ( Figure 1A) [10, 30-38] (reviewed in [3,4,9,18-20,39]). Increased TERTp methylation is typically recorded in >50% of TERT-expressing tumors and cell lines [10,[40][41][42][43][44][45][46][47]. Epigenetic regulation of TERTp is based on altered methylation patterns of specific regions. Hypomethylation of the region between −200 and −100 from the Translational Start site (TSS), encompassing the core promoter, enables binding of c-Myc and Sp-1, thus reactivating transcription. In contrast, the region spanning exon 1 (positions +1 to ±100 from the TSS) contains a binding site for the DNA insulator CTCF. Hypermethylation of this region disrupts binding of CTCF and therefore allows TERT transcription [41][42][43][44]. Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41][42][43][44].

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Section: Telomerase Reverse Transcriptase Promoter (Tertp) Mutationsmentioning

confidence: 95%

Section: Telomerase Reverse Transcriptase Promoter (Tertp) Mutationsmentioning

confidence: 99%

The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

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“…Following the above-stated results, we tested if hTERT promoter G>A mutations at the -124 or the -146 th bp position from TSS, frequently reported to be associated with human GBM, melanoma and other cancers 22,[48][49][50] , affected TRF2 binding. We first tested two GBM, U87MG and LN229, transformed cell lines with activated telomerase that had the -124G>A mutation in both cases 51,52 . In both cell types we could not detect any TRF2 occupancy at the hTERT promoter ( Figure 4G, H).…”

Section: Trf2 Occupancy Is Lost In Cancers With Htert Promoter Mutationsmentioning

confidence: 99%

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

Sharma

Mukherjee

Roy

et al. 2020

Preprint

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Tight regulatory mechanisms to maintain repression of human Telomerase (hTERT), the sole protein that synthesizes telomeres, is crucial for normal adult somatic cells. In contrast, enhanced telomerase activity and resulting pathological maintenance of telomeres, is widely understood as causal in >90% of human cancers. These implicate underlying mechanisms connecting hTERT regulation and telomeres, possibly through telomeric proteins, that remain unclear. In light of of recent work by us and others showing non-telomeric function of the telomere-binding protein TRF2, here we examined whether and how TRF2 affected hTERT regulation. Direct binding of TRF2spanning ~450 bp of the hTERT promoter from the Transcriptional Start Site (TSS)led to TRF2-dependent recruitment of the polycomb repressor complex PRC2 in both normal and cancer cells. This induced repressor histone modifications resulting in TRF2-dependent hTERT repression.Mutations in the hTERT promoter, found frequently in aggressive glioblastoma and reported to destabilize the G-quadruplex structure, resulted in loss of TRF2 binding and consequent hTERT over-expression. Conversely, using G-quadruplex-stabilizing ligands we regained TRF2 binding, hTERT re-suppression, in highly proliferating glioblastoma cells with telomerase hyperactivation due to hTERT promoter mutations. Together, results herein demonstrate direct control of hTERT through TRF2 in a G-quadruplex-dependent mannerimplicating mechanisms of how telomerase regulation might be linked to telomeres in normal and cancer cells. IntroductionTelomeres, comprising of (GGGTTA) n repeats in complex with telomere-binding proteins, at the end of human chromosomes are essential for genome stability 1-6 . The only protein that can replicate telomeric DNA is telomerase -a ribonucleoprotein complex of the reverse transcriptase (hTERT) and RNA the template (hTERC). In adult somatic cells, hTERT is kept trasncriptionally repressed.Resulting loss of telomeres with each replication cycle leads to replicative senescence, much like a 'molecular clock' that helps maintain cellular homeostasis. Deregulation or loss of hTERT repression, which results in aberrant maintenance of telomeres, has been causally associated to initiation/progression of more than 90% human cancers 7,8 . Although, these suggest tight control of telomerase might be linked to telomeres -the role of telomeres or telomere-binding factors in regulation of hTERT remains poorly explored.Relatively recent work by others and us showing non-telomeric binding of telomere-binding proteins, TRF1, TRF2 and RAP1, is of interest in this context. Genome wide RAP1 association has been reported in mouse and human cells while TRF1/TRF2 binding has been demonstrated in human cells 9-11 . Notably, we found about 20000 TRF2 binding sites spread throughout the genome where TRF2-mediated promoter epigenetics and gene regulation was evident. A large fraction of the TRF2 binding sites coincided with potential DNA secondary structure G-quadruplex-forming sequences 12 .Further, ...

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“…The human meningioma cell line IOMM-Lee (derived from a grade III meningioma) [ 18 , 19 ], courtesy of Dr. Randy Jensen (University of Utah), was cultured in growth media composed of RPMI 1640 Medium, 10% fetal bovine serum, 2 mM L-glutamine, 100 IU/mL of penicillin, and 100 μg/mL of streptomycin (Life Technology, Grand Island, USA). Cultured cells were maintained at 37° in a 5% CO 2 atmosphere.…”

Section: Methodsmentioning

confidence: 99%

Osteoglycin promotes meningioma development through downregulation of NF2 and activation of mTOR signaling

et al. 2017

Cell Commun Signal

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BackgroundMeningiomas are the most common primary intracranial tumors in adults. While a majority of meningiomas are slow growing neoplasms that may cured by surgical resection, a subset demonstrates more aggressive behavior and insidiously recurs despite surgery and radiation, without effective alternative treatment options. Elucidation of critical mitogenic pathways in meningioma oncogenesis may offer new therapeutic strategies. We performed an integrated genomic and molecular analysis to characterize the expression and function of osteoglycin (OGN) in meningiomas and explored possible therapeutic approaches for OGN-expressing meningiomas.Methods OGN mRNA expression in human meningiomas was assessed by RNA microarray and RNAscope. The impact of OGN on cell proliferation, colony formation, and mitogenic signaling cascades was assessed in a human meningioma cell line (IOMM-Lee) with stable overexpression of OGN. Furthermore, the functional consequences of introducing an AKT inhibitor in OGN-overexpressing meningioma cells were assessed.ResultsOGN mRNA expression was dramatically increased in meningiomas compared to a spectrum of other brain tumors and normal brain. OGN-overexpressing meningioma cells demonstrated an elevated rate of cell proliferation, cell cycle activation, and colony formation as compared with cells transfected with control vector. In addition, NF2 mRNA and protein expression were both attenuated in OGN-overexpressing cells. Conversely, mTOR pathway and AKT activation increased in OGN-overexpressing cells compared to control cells. Lastly, introduction of an AKT inhibitor reduced OGN expression in meningioma cells and resulted in increased cell death and autophagy, suggestive of a reciprocal relationship between OGN and AKT.ConclusionWe identify OGN as a novel oncogene in meningioma proliferation. AKT inhibition reduces OGN protein levels in meningioma cells, with a concomitant increase in cell death, which provides a promising treatment option for meningiomas with OGN overexpression.Electronic supplementary materialThe online version of this article (10.1186/s12964-017-0189-7) contains supplementary material, which is available to authorized users.

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High incidence of TERT mutation in brain tumor cell lines

Cited by 27 publications

References 25 publications

The Solo Play of TERT Promoter Mutations

The Solo Play of TERT Promoter Mutations

Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2

Osteoglycin promotes meningioma development through downregulation of NF2 and activation of mTOR signaling

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