Abstract
Telomeres are nucleoprotein structures located at the ends of linear chromosomes. In most human adult normal somatic cells, telomeres shorten after each cellular division. This shortening ultimately leads to senescence and/or apoptosis. By contrast, in most cancer cells, telomerase activation compensates this loss and confers to these cells their infinite cell proliferation potential. Neuroblastoma (NBL) is a malignant tumor of the peripheral sympathetic nervous system and the most frequent extracranial solid tumor of childhood. NBLs are remarkably heterogeneous both at the levels of biology, genetic and clinical courses. Indeed, some of NBLs can regress spontaneously or after a mild treatment, while others are in the high-risk category with poor prognosis. The molecular bases underlying this heterogeneity are poorly understood. MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-derived Homolog) amplification, recognized as strongly associated with unfavorable patient outcome, is found in only 40% of the high-risk disease, indicating the involvement of other mechanisms. Recent observations suggest that telomerase expression and telomere dysfunctions may be one critical step in NBL development. This review provides recent insights on telomeres/telomerase regulation in NBL. Because of their involvement in the tumor cell biology, telomere and telomerase are currently at the core of new drug development.
Keywords
- telomerase
- telomeres
- regulation
- therapies
- neuroblastoma
1. Introduction
Cancer development is a multistep process requiring genetic and epigenetic events leading to the deregulation of the expression of key genes. Among these genes, telomerase, by its action on telomere maintenance, plays a major contribution in carcinogenesis and drug resistance. This enzyme is activated in almost 90% of cancers, including neuroblastoma (NBL).
Neuroblastoma is a malignant tumor of the peripheral sympathetic nervous system and the most common extracranial solid tumor in childhood [1, 2]. NBL is remarkably heterogeneous and displays a wide spectrum of differentiation stages from benign ganglioneuroma and well-differentiated tumors to undifferentiated malignant NBL. NBL is also a heterogeneous disease in terms of outcome and response to treatments: from spontaneous regression to resistance to all known treatments. In about 60% of the cases, NBL is diagnosed as a disseminated high-risk disease (stage 4), and most are diagnosed after 18 months of age. Genomic amplification of
Recently, the next-generation sequencing has shown that high-risk NBLs are characterized by defects that in common lead to the activation of telomere maintenance pathways supporting the idea that targeting these pathways will benefit to the patients [9, 10].
Many excellent recent reviews [11, 12] already exist on telomeres and telomerase in many aspects (structure and functions, regulation, and epigenetic control). This paper will therefore briefly review the recent knowledge on this topic, then, it will focus on the mechanisms of telomerase reactivation and telomere length maintenance in NBL, and discuss how these regulatory mechanisms can be targeted or “manipulated” for therapeutic purposes to modify cell fate and anticancer drug response in NBL.
2. Telomeres and telomerase
2.1. Telomeres
Every normal human somatic cell has a molecular clock for dividing, a process discovered by Leonard Hayflick, half a century ago, who observed that diploid cells in culture can divide only a limited number of times before stopping in a state known as the cellular senescence or the “Hayflick limit” [13]. In eukaryotic organisms, conventional DNA polymerases alone cannot fully replicate the ends of linear chromosomes, called telomeres. Therefore, telomere ends are progressively shortened after each cellular division [14, 15]. This leads to genomic instability and senescence or apoptosis.
Telomeres are specialized nucleoprotein structures made of 10–15 kb of short non-protein-coding repetitive 5′-TTAGGG-3′ DNA sequences. Telomeric DNA is mainly double-stranded, terminating in a single-stranded 3′ G-rich overhang of 150–200 nucleotides (nt) [16, 17]. These double-stranded repeats have one guanosine-rich strand (G-strand) copied by the lagging-strand replication, and one cytosine-rich strand (C-strand) synthesized by leading-strand replication. The telomeric DNAs are bound by shelterin protein complexes consisting of telomeric repeat factors 1 and 2 (TRF1 and TRF2), repressor/activator protein 1 (RAP1), TRF1- and TRF2-interacting nuclear protein 2 (TIN2), tripeptidyl-peptidase 1 (TPP1), and protection of telomeres 1 (POT1) [18, 19]. TRF1 and TRF2 bind to the double-stranded telomere DNA repeats, whereas POT1 binds to the single-stranded G-rich overhang. The three remaining proteins of the shelterin complex act as adaptors to mediate the interactions between the complex constituents: POT1 interacts with TPP1, a ternary complex of other proteins (TINT1/PTOP/PIP1), which interacts in turn with TIN2 that plays a key role in stabilizing the shelterin complex
Due to the tandem organization of the G-rich telomeric DNA, the telomeres can form specialized four-stranded helical structures that involve Hoogsten-type base pairing between four guanines, named G-quadruplex (or G4) [20]. Alternatively, the G-strand overhang is also involved in the formation of the t-loop in which it invades the double-stranded region [21]. It has been hypothesized that those structures, which are not mutually exclusive, are able, by sequestering the 3′ end, to prevent the extension of the telomeres by telomerase.
Besides their role of capping chromosomes and protecting them from being recognized as DNA breaks [22], telomeres ensure proper chromosome segregation during mitosis [23] as well as transcriptional silencing of genes located close to them. Indeed, telomere shortening can alter gene expression by a process named telomere position effect (TPE) [24]. This process leads to the reversible silencing of genes near the telomere and thus is dependent on telomere length. In yeast, TPE can repress genes located up to 20 kb from the end [25, 26]. Recently, using a Hi-C (chromosome capture followed by high-throughput-sequencing) technique, three genes located at three different subtelomeric ends (1p, 6p, and 12p) were reported to have their expression altered with telomere length:
Two mechanisms of telomere maintenance have been identified in humans: the telomerase-mediated maintenance observed in 90% of cancers and, in the remaining 10%, the alternative lengthening of telomeres (ALT), which depends on homologous recombination [29, 30].
2.2. Telomerase: a ribonucleoprotein complex with multiple functions
Elizabeth Blackburn and her graduate student Carol Greider (2009 Nobel Prize in Physiology or Medicine) who worked on the ciliated protozoan
Telomerase is an RNA-dependent DNA polymerase that plays a key role in carcinogenesis. By synthesizing telomeric DNA at the termini of chromosomes and stabilizing telomere lengths, it overcomes the senescence barrier due to the progressive telomere shortening associated with cell divisions [33]. Normal human somatic cells have very low or undetectable telomerase activity. By contrast, this activity has been detected in a wide range of human cancers (85–90%), in stem cells and adult germline tissues [34, 35]. By its action on telomeres, this enzyme confers to cancer cells their infinite cell proliferation potential and controls cell survival [36–38]. Telomerase is believed to be a significant target in cancer therapy since its upregulation appears to be a feature of malignant cells.
The human telomerase is a ribonucleoprotein enzyme (127 kDa) composed of at least two components, a catalytic subunit, telomerase reverse transcriptase (hTERT), and a template RNA component (hTR) (Figure 1).
hTR is a non-polyadenylated 451-nt long non-coding RNA containing eight conserved regions (CR1–CR8) that acts mainly as a template for the synthesis of the telomeric DNA. hTR binds hTERT
Loss-of-function mutations of either
Besides its canonical role, accumulated evidence indicates that telomerase elicits other functions in several essential cell-signaling pathways, including apoptosis, differentiation, DNA damage responses, and regulation of gene expression [45–50]. Even though these functions appear independent of telomerase activity, it is not excluded that some transient effect at telomeres can affect chromatin structure and gene expression. One example of these non-canonical functions of hTERT is the demonstration that hTERT binds NF-κB p65 subunit and regulates some of its target genes such as
Recently, it has been shown that BRG1 plays an essential role in maintaining the proliferation and viability of NBL cells. Interestingly, BRG1 is consistently upregulated in several NBL cell lines and in advanced stages of NBLs. Furthermore, high BRG1 levels have been correlated with poor patient outcome [59]. Therefore, BRG1 inhibition could be a possible new line of treatment for high-risk NBL patients. In view of these observations, the relationship between BRG1 and hTERT in NBL should be investigated.
2.3. Human hTERT regulation
Given the key role of telomerase in malignant transformation and tumor progression, great efforts have been deployed to unravel the mechanisms underlying telomerase activation.
2.3.1. hTERT gene and its promoter
The
Telomerase activity is generally well correlated with
The
2.3.2. Transcriptional regulators of hTERT
The factors that bind
Recent articles have already reviewed exhaustively the roles of specific regulatory factors of
2.3.2.1. c-Myc/Max/Mad-1
c-Myc and its dimerization partner Max (Myc-associated factor X) bind to regulatory elements called E-boxes and recruits histone acetyltransferases in order to activate the transcription of various genes, including
Numerous factors thereby are able to indirectly upregulate
Despite the strong evidence of the action of c-Myc as a transcriptional activator of
NBL cells generally do not express c-Myc but N-MYC, a protein belonging to the same family. c-Myc and N-MYC are encoded by different genes but have similar structures and domains. As c-Myc, N-MYC protein was shown to be recruited to the
2.3.2.2. Specificity protein 1 (Sp1)
Sp1 is a transcription factor that binds to GC-box motifs in the promoter of
It is important to note that this GC-rich region of
2.3.2.3. Nuclear factor κ-light-chain-enhancer of activated B cells (NF-kB)
NF-kB is a transcription factor complex playing a role in telomerase expression and activity either directly through its binding on
2.3.2.4. Upstream stimulatory factor (USF) proteins
As c-Myc, USF proteins bind directly to E-box motifs on the core promoter of
2.3.2.5. CCCTC-binding factor
CTCF transcription factor binds at the beginning of exon 1 (+4 to +39 bp) and near the beginning of exon 2 (+422 to +440 bp) relative to the ATG in
2.3.2.6. Wilms, tumor protein 1
WT1 is described as a repressor of
2.3.3. hTERT promoter mutations
Recently, hotspot promoter recurrent mutations were identified first in sporadic and familiar malignant melanoma [88, 89]. These mutations, which cause an adenine-to-cytosine (A>C) mutation or a cytosine-to-thymine (C>T) transition at chromosome 5: 1,295,161, 1,295,228, and 1,295,250 (−57, −124, and −146 bp upstream of the ATG translation start codon), are named −57A>C (or A161C), −124C>T (or C228T), and −146C>T (or C250T), respectively. From there, the
Mechanistically, −124C>T or −146C>T mutation generates an 11-base nucleotide stretch (5′-CCCCTTCCGGGG-3′), which contains a consensus-binding site (GGAA in reverse complement) for ETS family transcription factors [99]. It was shown that the multimeric GA-binding protein (GABP), an ETS family transcription factor, was specifically recruited to the mutant rather than wild-type
Genome-wide association studies revealed the presence of single-nucleotide polymorphisms (SNPs) within the
While
2.3.4. Epigenetic regulation of hTERT transcription
The
Considering the methylation pattern categorized in different cell lines, it is possible to narrow the promoter to only two regions: one methylated, sometimes hypermethylated (from −650 to −200 bp from ATG) and one unmethylated or only slightly methylated (from −200 to +100 bp) [86, 106–110].
It is known that DNA methylation at gene promoter plays a major role in transcription factor binding. For example, hypomethylation at the
Besides DNA methylation, histones contribute to chromatin organization. Modifications can occur to their amino acid tails: methylation and acetylation are the most common. In general, methylation of histone 3 at its lysine 4 (H3K4) and hyperacetylation of histones are signs of hypo- or unmethylated DNA and active transcription gene. On the contrary, methylation of lysine 9 and 27 of histone 3 (H3K9 and H3K27, respectively) and hypoacetylation of histones are signs of hypermethylated DNA, so inactive transcription gene [110].
2.4. Human TR regulation
As
3. Telomeres and telomerase in neuroblastoma
3.1. Telomerase as a biological marker and predictive factor in neuroblastoma
Several distinguishable groups in NBL have been identified based on their telomere biology and telomerase activation suggesting that telomerase expression may be one critical step in the development of neuroblastoma [5]. High telomerase activity allowing the maintenance of telomere length has been previously reported to correlate with advanced stages of the disease and with poor prognosis [5, 117–121]. By contrast, tumors without detectable telomerase activity showed favorable outcomes and some tumors regressed or matured [122]. This phenomenon of spontaneous regression led to propose a specific pattern of the metastatic disease called stage 4S. Children with stage 4S were restricted to infants aged less than 12 months at diagnosis, had generally small primary tumors with dissemination limited to the liver and skin and minimum bone marrow involvement [123]. The mechanisms involved in this regression remain to be elucidated. The expression of the alternate splice variants of
Several mechanisms have been proposed to explain the phenomenon of spontaneous regression. These include the neurotrophin receptor signaling when deprivation in nerve growth factor occurs, immune-mediated killing by anti-neural antibodies in patients, epigenetic regulation of gene expression through DNA methylation, histone modifications or chromatin remodeling, and finally telomere shortening and consequently apoptosis. Indeed, most of the tumor samples from 4S NBL have low telomerase activity or short telomeres [5]. This mechanism is further supported by Samy et al. who showed that a neuroblastoma cell line transfected by a dominant-negative form of human telomerase was more prone to apoptosis and had reduced tumorigenicity in a mouse xenograft model compared to untransfected neuroblastoma cells [125].
A correlation between
Even though the main role of telomerase is to maintain telomere length in tumors, non-canonical functions could also promote tumor growth and contribute to poor prognosis in primary NBLs (Wnt signaling, DNA repair, genomic instability, apoptosis, and escape from oncogene-induced senescence) [117].
Using a novel approach of three-dimensional (3D) telomere quantitative fluorescence
3.2. Potential mechanisms of hTERT activation and/or telomere maintenance mechanisms in neuroblastoma
The mechanisms by which telomerase activity is activated in high-stage NBL remain elusive. However, recent studies have shed some light on this important question. Although some controversies may remain, hTERT expression upregulation may occur through at least two pathways:
3.2.1. MYCN amplification
A recent study shows that
3.2.2. hTERT promoter mutations
Although hotspot mutations in
3.2.3. hTERT gains
Chromosome 5p is often amplified in NBL, and focal
3.2.4. hTERT rearrangements
Recent whole-genome sequencing of primary neuroblastoma, performed by two independent groups, discovered recurrent genomic rearrangements in a 70-kb region proximal to
Indeed, in the first study [10], the authors were searching for structural alterations that might occur in high-risk NBL and, analyzing 56 tumors, they identified 4 locations exhibiting clustered breakpoints. These are related to
In a similar whole-sequencing study [9] screening 108 NBLs, structural rearrangements of
These results have been major advances in our understanding of NBL genetic and biology placing telomere biology at the core of this pathology.
3.2.5. Small nucleolar ribonucleoproteins (snoRNPs)
A recent study reported that the expression of proteins involved in the formation and stabilization of snoRNP complex (including DKC1, GAR1, and NHP2 proteins) is elevated in high-risk NBL and associated with poor prognosis. Furthermore, this study shows a positive correlation between DKC1 expression and telomerase activity. This increase is associated with an increase of
3.2.6. ALT and neuroblastoma: ATRX (alpha thalassemia/mental retardation syndrome, X-linked) mutations
Telomere length does not necessarily correlate with telomerase activity [141]. Recently, it has been reported that some neuroblastomas (generally associated with unfavorable NBL in older children without
3.2.7. ARID1A and ARID1B
Next-generation sequencing, genome-wide rearrangements analyses, and targeted analysis of specific genomic loci of 71 NBL patients identified mutations in chromatin-remodeling complexes encoded by
In conclusion, it is important to note that through either
Altogether, these observations provide new important mechanisms that could be targeted in new therapeutic strategies to treat the most aggressive forms of neuroblastoma.
4. Telomerase, a target for cancer therapeutics
That, on one hand, both
Regarding NBL, perhaps future attempts could be to target specifically N-MYC protein in patients who have NBL with
The recent identification of
Telomerase expression was proposed as a selectively targetable mechanism for retinoids and specifically all
5. Conclusions
Several potential chemotherapy strategies based on telomerase and telomere biology have been developed and explored by pharmaceutical and biotechnology companies [163]. However, in spite of ever-growing knowledge on telomere and telomerase biology, a number of questions remain to be answered as most of these numerous strategies are not yet clinically available because of a weak efficiency and/or a high toxicity. Therefore, to develop agents that will be effective, we need a sharper picture of how the enzyme functions and how we can manage to target specifically and destabilize telomeres in cancer cells. Epigenetic therapies aimed at counteracting the genetic alterations (mutations) are emerging alternatives against aggressive tumors.
Telomerase regulation is highly complex, involving the interplay between numerous biological and molecular processes. Despite the extensive studies that have been already done, a lot more is necessary to unravel the mechanisms underlying the switching off/on of
First, telomerase repeated amplification protocol (TRAP) assay is a rather artificial assay to quantify telomerase activity; it is based on a quantitative real-time polymerase chain reaction (PCR) method that measures only the capacity of the telomerase reverse transcriptase to elongate artificial telomeric substrates without giving any measurement of the other functions of this protein. To date, no assay exists to evaluate the non-conventional functions of hTERT.
Second,
Third,
Finally, due to the low expression of telomerase even in cancer cells, the detection of telomerase by western blot or fluorescence is puzzling. In addition, commercially available anti-hTERT antibodies are still a problem with specificity [164]. Because of these limitations, several published studies used overexpressed hTERT protein (generally tagged). However, the unusually high concentration of the protein due to the overexpression could alter the dynamic and the localization of the protein compared to the endogenous protein leading to misinterpretations.
Since the first paper published in 1995 [5], very few scientific advances have been done on a potential involvement of telomere/telomerase in NBL biology. However, the recent findings highlighting the role of telomere/telomerase biology in high-risk NBL will definitely impact the research in this pathology as well as in other cancers and help to develop new therapeutic strategies.
Acknowledgments
The work of the authors was supported by grants from the French National Institute of Health and Medical Research (INSERM), the National Center for Scientific Research (CNRS), the Ligue Nationale contre le Cancer, the Fondation de France (n° 201300038226), the French National Research Agency (ANR), Gefluc, Agence Universitaire de la Francophonie (AUF), Hubert Curien Partnership (PHC-CEDRE), and Ministère de l’Enseignement Supérieur et de la Recherche (MESR). Yann Blondin is acknowledged for his help in preparing Figure 1.
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Notes
- E. Ségal-Bendirdjian et al., unpublished results.