Gene Summary

Gene:TERF2; telomeric repeat binding factor 2
Aliases: TRF2, TRBF2
Summary:This gene encodes a telomere specific protein, TERF2, which is a component of the telomere nucleoprotein complex. This protein is present at telomeres in metaphase of the cell cycle, is a second negative regulator of telomere length and plays a key role in the protective activity of telomeres. While having similar telomere binding activity and domain organization, TERF2 differs from TERF1 in that its N terminus is basic rather than acidic. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:telomeric repeat-binding factor 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (30)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA Methylation
  • Osteosarcoma
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Telomeric Repeat Binding Protein 1
  • Down-Regulation
  • DNA Repair
  • Cell Proliferation
  • Nuclear Proteins
  • Prostate Cancer
  • Genetic Predisposition
  • TNF
  • FISH
  • Chromosome 16
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • DNA-Binding Proteins
  • Telomere
  • Translocation
  • Neoplasm Proteins
  • Chromosome Aberrations
  • Up-Regulation
  • Messenger RNA
  • Cancer Gene Expression Regulation
  • Telomere Homeostasis
  • Telomerase
  • Cellular Senescence
  • Breast Cancer
  • Transferrin
  • bcl-X Protein
  • p53 Protein
  • Cell Cycle Proteins
  • Single Nucleotide Polymorphism
  • Biomarkers, Tumor
  • DNA Damage
  • Staging
  • Chromosomal Instability
  • Apoptosis
  • Risk Factors
  • Genomic Instability
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TERF2 (cancer-related)

Shen C, Chen F, Wang H, et al.
The Pinx1 Gene Downregulates Telomerase and Inhibits Proliferation of CD133+ Cancer Stem Cells Isolated from a Nasopharyngeal Carcinoma Cell Line by Regulating Trfs and Mad1/C-Myc/p53 Pathways.
Cell Physiol Biochem. 2018; 49(1):282-294 [PubMed] Related Publications
BACKGROUND/AIMS: Cancer stem cells (CSCs) are important factors for the continuous growth, recurrence, and metastasis of malignant tumors. They are responsible for the ineffectiveness of traditional radiotherapy and chemotherapy toward malignant tumors. Currently, stem cells or side-population cells have been isolated from many cancer cell lines and malignant tumor tissues, including nasopharyngeal carcinoma. Exploring the biological characteristics of CSCs for CSC-targeted therapy has gained importance. CSCs possess higher telomerase activity; thus, the use of the gene encoding telomerase inhibitor PinX1 gene to target telomerase in CSCs and inhibit proliferation, invasion, and metastasis of CSCs has become an important means for the treatment of malignant tumors. PinX1 may regulate complex pathways, including TRF1, Mad1/c-Myc, and p53.
METHODS: In this study, nasopharyngeal CD133+ CSCs were sorted using CD133 immunomagnetic beads by flow cytometry The successful isolation of CD133+ CSCs was confirmed by examining their surface markers, namely CD44, NaNOG, and SOX2 as well as their ability to undergo in vivo tumorigenesis and in vitro sphere formation, proliferation, migration, and invasion. In addition, CD133+ CSCs were transfected with the constructed PinX1 overexpression plasmid or siRNA and the resulting effects on their proliferation, migration, invasion, and apoptosis were detected using cell counting kit-8 (CCK-8), transwell assay, and scratch test, respectively. Furthermore, their effects on mRNA and protein levels of TRF1, TRF2, Mad1, c-Myc, and p53 were examined using quantitative real-time PCR and western blot, respectively.
RESULTS: The overexpression of PinX1 in CD133+ CSCs significantly decreased hTERT (P < 0.001), inhibited proliferation, migration, and invasion, induced apoptosis, and significantly decreased c-Myc mRNA levels (P < 0.001), while it increased TRF1, Mad1, and p53 mRNA levels (all P < 0.001). On the other hand, PinX1 silencing in CD133+ CSCs significantly decreased TRF1, Mad1, and p53 mRNA levels (all P < 0.01), while it increased hTERT and c-Myc mRNA levels (all P < 0.05).
CONCLUSION: These results indicate that PinX1 downregulates telomerase activity in CD133+ CSCs, inhibits its proliferation, migration, and invasion, and induces apoptosis possibly through TRF1, Mad1/c-Myc, and p53-mediated pathways.

Wang H, Ni J, Guo X, et al.
Shelterin differentially respond to oxidative stress induced by TiO
Biochem Biophys Res Commun. 2018; 503(2):697-702 [PubMed] Related Publications
Titanium dioxide nanoparticles (TiO

Saha A, Roy S, Kar M, et al.
Role of Telomeric TRF2 in Orosphere Formation and CSC Phenotype Maintenance Through Efficient DNA Repair Pathway and its Correlation with Recurrence in OSCC.
Stem Cell Rev Rep. 2018; 14(6):871-887 [PubMed] Related Publications
The major problem to effective treatment of oral cancer is the presence of therapy resistance. Presence of cancer stem cell in the bulk of tumor have been implicated in therapeutic resistance. In this study, we report a non-telomeric role of TRF2 in formation of oral cancer spheroids and CSC phenotype maintenance via an efficient DNA damage repair mechanism in the presence of chemotherapeutic insult. We report reduced sphere formation efficiency and reduced spheroid size in TRF2 silenced oral cancer cell lines. TRF2 silenced orospheres further reported reduced proliferative capacity as compared to non-silenced orospheres. Furthermore, TRF2 silencing hampered the migratory potential of oral cancer cell line and also reduced the expression of several CSC markers like CD44, Oct4, Sox2, KLF4 and c-Myc along with β-catenin and hTERT molecules both in Cal27 cell line and generated orospheres. TRF2 silencing impaired efficient DNA damage repair capacity of non-orospheric and orospheric cells and repressed ERCC1 expression levels when treated with Cisplatin. TRF2 overexpression was also observed to correlate with poor overall survival and disease relapse of OSCC patients. In silico studies further identified several amino acid residues that show high binding affinity and strong protein-protein interactions among TRF2 and CSC marker KLF4. Hence, our report confirms a non-telomeric role of TRF2 in spheroid generation, maintenance of CSC phenotype and efficient DNA damage repair capacity contributing to chemotherapy resistance in oral cancer cell line. We further iterate the use of TRF2 as a prognostic marker in OSCC for faster detection and improved survival.

Aljarbou F, Almousa N, Bazzi M, et al.
The expression of telomere-related proteins and DNA damage response and their association with telomere length in colorectal cancer in Saudi patients.
PLoS One. 2018; 13(6):e0197154 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer is the leading cause of cancer-related deaths in Saudi Arabia. Cancer has a multifactorial nature and can be described as a disease of altered gene expression. The profiling of gene expression has been used to identify cancer subtypes and to predict patients' responsiveness. Telomere-associated proteins that regulate telomere biology are essential molecules in cancer development. Thus, the present study examined their contributions to colorectal cancer progression in Saudi patients.
METHODS: The expression of hTERT, TRF1, TRF2, POT1, ATR, ATM, Chk1 and Chk2 were measured via real-time PCR in matched cancerous and adjacent tissues of CRC patients. The protein level of hTERT, TRF1, TRF2, ATR, ATM, Chk1 and Chk2 were measured using immunohistochemistry. A region of hTERT core promoter was sequenced via Sanger sequencing. Methylation of CTCF binding site was examined via methylation-specific PCR. Finally, the length of telomere was estimated using q-PCR.
RESULTS: Our results showed that POT1, ATR, Chk1 and Chk2 show increased expression in CRC relative to the adjacent mucosa. The expression levels of each gene were associated with clinicopathological characteristics of patients with CRC. There was a positive correlation between the age of the patients and hTERT expression. Regarding tumor site, telomere length, ATR, ATM and Chk1 were shown to be altered. No somatic mutation was detected in hTERT core promoter, and no differences in methylation patterns at CTCF binding site in the promoter between normal and cancer tissues.
CONCLUSION: Analysis of targeted genes expression in colorectal cancer based on the clinical variables revealed that tumor location and age could have a role in gene expression and telomere length variations and this could be taken under consideration during CRC diagnosis and therapy. Other epigenetic mechanisms could influence hTERT expression in cancers. Our findings warrant further validation through experiments involving a larger number of patients.

Hu WL, Jin L, Xu A, et al.
GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability.
Nat Cell Biol. 2018; 20(4):492-502 [PubMed] Related Publications
The list of long non-coding RNAs (lncRNAs) involved in the p53 pathway of the DNA damage response is rapidly expanding, but whether lncRNAs have a role in maintaining the de novo structure of DNA is unknown. Here, we demonstrate that the p53-responsive lncRNA GUARDIN is important for maintaining genomic integrity under steady-state conditions and after exposure to exogenous genotoxic stress. GUARDIN is necessary for preventing chromosome end-to-end fusion through maintaining the expression of telomeric repeat-binding factor 2 (TRF2) by sequestering microRNA-23a. Moreover, GUARDIN also sustains breast cancer 1 (BRCA1) stability by acting as an RNA scaffold to facilitate the heterodimerization of BRCA1 and BRCA1-associated RING domain protein 1 (BARD1). As such, GUARDIN silencing triggered apoptosis and senescence, enhanced cytotoxicity of additional genotoxic stress and inhibited cancer xenograft growth. Thus, GUARDIN may constitute a target for cancer treatment.

Chhabra G, Wojdyla L, Frakes M, et al.
Mechanism of Action of G-Quadruplex-Forming Oligonucleotide Homologous to the Telomere Overhang in Melanoma.
J Invest Dermatol. 2018; 138(4):903-910 [PubMed] Related Publications
T-oligo, a guanine-rich oligonucleotide homologous to the 3'-telomeric overhang of telomeres, elicits potent DNA-damage responses in melanoma cells; however, its mechanism of action is largely unknown. Guanine-rich oligonucleotides can form G-quadruplexes (G4), which are stabilized by the hydrogen bonding of guanine residues. In this study, we confirmed the G4-forming capabilities of T-oligo using nondenaturing PAGE, nuclear magnetic resonance, and immunofluorescence. Using an anti-G-quadruplex antibody, we showed that T-oligo can form G4 in the nuclei of melanoma cells. Furthermore, using DNase I in a nuclease degradation assay, G4-T-oligo was found to be more stable than single-stranded T-oligo. G4-T-oligo had decreased antiproliferative effects compared with single-stranded T-oligo. However, G4-T-oligo has similar cellular uptake as single-stranded T-oligo, as shown by FACS analysis. Inhibition of JNK, which causes DNA damage-induced apoptosis, partially reversed the antiproliferative activity of T-oligo. T-oligo also inhibited mRNA expression of human telomerase reverse transcriptase, a catalytic subunit of telomerase that was reversed by JNK inhibition. Furthermore, two shelterin complex proteins TRF2/POT1 were found to be up-regulated and bound by T-oligo, suggesting that T-oligo may mediate dissociation of these proteins from the telomere overhang. These studies show that T-oligo can form a G-quadruplex and that the antitumor effects of T-oligo may be mediated through POT1/TRF2 and via human telomerase reverse transcriptase inhibition through JNK activation.

Kim W, Shay JW
Long-range telomere regulation of gene expression: Telomere looping and telomere position effect over long distances (TPE-OLD).
Differentiation. 2018 Jan - Feb; 99:1-9 [PubMed] Free Access to Full Article Related Publications
The human cellular reverse transcriptase, telomerase, is very tightly regulated in large long-lived species. Telomerase is expressed during early human fetal development, is turned off in most adult tissues, and then becomes reactivated in almost all human cancers. However, the exact mechanism regulating these switches in expression are not known. We recently described a phenomenon where genes are regulated by telomere length dependent loops (telomere position effects over long distances; TPE-OLD). The hTERT gene is ~ 1.2Mb from the human chromosome 5p end. We observed that when telomeres are long hTERT gene expression is repressed and a probe next to the 5p telomere and the hTERT locus are spatially co-localized. When telomeres are short at least one of the hTERT alleles is spatially separated from the telomere, developing more active histone marks and changes in DNA methylation in the hTERT promoter region. These findings have implications for how cells turn off telomerase when telomeres are long during fetal development and how cancer cells reactivate telomerase in cells that have short telomeres. In addition to TPE-OLD, in proliferating stem cells such as activated T-lymphocytes, telomerase can be reversibly activated and silenced by telomere looping. In telomerase positive cancer cells that are induced to differentiate and downregulate telomerase, telomere looping correlates with silencing of the hTERT gene. These studies and others support a role of telomeres in regulating gene expression via telomere looping that may involve interactions with internal telomeric sequences (ITS). In addition to telomere looping, TPE-OLD may be one mechanism of how cells time changes in physiology without initiating a DNA damage response.

Kumar R, Khan R, Gupta N, et al.
Identifying the biomarker potential of telomerase activity and shelterin complex molecule, telomeric repeat binding factor 2 (TERF2), in multiple myeloma.
Leuk Lymphoma. 2018; 59(7):1677-1689 [PubMed] Related Publications
Telomere length (TL) is maintained by telomere capping protein complex called shelterin complex. We studied the possible involvement and biomarker potential of shelterin complex molecules in naive multiple myeloma (MM) patients and controls. TL, relative telomerase activity (RTA), real-time PCR and Western blotting were performed in bonemarrow sample of 70 study subjects (patients = 50; controls = 20). Significantly lowered mean TL, increased RTA and higher mRNA expression of shelterin molecules were observed in patients, while PIN2/TERF1 interacting telomerase inhibitor 1 (PINX1) showed lower mRNA expression. Significantly increased protein expression of telomeric repeat binding factor 2 (TERF2), protection of telomeres 1, adrenocortical dysplasia homolog, Tankyrase 1 and telomere reverse transcriptase were observed in MM patients. Significant correlation was observed among genes and of genes with clinical parameters. In conclusion, our findings showed alteration of these molecules at mRNA and protein levels suggested their involvement in disease progression. Optimal sensitivity and specificity of TERF2 and RTA on receiver operating characteristics curve analysis and univariate analysis demonstrated their biomarkers potential in better prediction of disease course.

Chen W, Wang Y, Li F, et al.
Expression of Telomere Repeat Binding Factor 1 and TRF2 in Prostate Cancer and Correlation with Clinical Parameters.
Biomed Res Int. 2017; 2017:9764752 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The objective of this study was to investigate the expression of telomere repeat binding factor 1 (TRF1) and TRF2 in prostate cancer and their relationships with clinicopathological features.
METHODS: In total 50 prostate cancer tissues and paired benign prostate hyperplasia tissues were analyzed. The telomere-binding proteins TRF1 and TRF2 were measured using immunohistochemical method. Correlation analyses were used to evaluate the association between immunohistochemical score and clinical parameters.
RESULTS: The expression of TRF1 was significantly higher in prostate cancer tissue than in benign prostate hyperplasia tissue (
CONCLUSION: Both TRF1 and TRF2 were overexpressed in prostate cancer. There was no specificity of TRF2 in prostate cancer, while TRF1 may be associated with prostate cancer progression.

Ishdorj G, Kost SEF, Beiggi S, et al.
A novel spliced variant of the TIN2 shelterin is present in chronic lymphocytic leukemia.
Leuk Res. 2017; 59:66-74 [PubMed] Related Publications
The shelterin proteins play important roles in telomere maintenance and genome stability. These proteins have been found to be mutated in many cancers including CLL. Herein, we demonstrate here the presence of a novel spliced isoform of TIN2S in chronic lymphocytic leukemia (CLL), related to deletion of exon 2 in the TIN2 gene. The expressions of spliced TIN2S mRNA varied widely in CLL and there was an inverse relationship between the mRNA levels of full-length TIN2S and the spliced moiety. Small amounts of spliced TIN2S were also observed in normal B cells but not in T cells. Spliced TIN2S appeared dysfunctional, as immunoprecipitation studies showed the typical association of TRF2 and TIN2 in normal lymphocytes but not in CLL cells. Moreover, whereas TRF2 localized to the nucleus in normal lymphocytes, it was present in both nuclei and cytoplasm in CLL cells. The levels of spliced TIN2S increased with age and in 3 of 8 patients increased over time. The presence of the spliced variant failed to be related to telomere length in CLL suggesting other functions for this protein. Further studies are required to determine the etiology and biological significance of this unique spliced TIN2S variant.

Lee WP, Lan KH, Li CP, et al.
The telomere-binding protein TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine.
Biochim Biophys Acta Mol Basis Dis. 2017; 1863(4):917-928 [PubMed] Related Publications
Gemcitabine and capecitabine are two effective anticancer agents against solid tumors. The pharmacological mechanisms have been known as incorporation into DNA and thereby inhibition of DNA synthesis. When used as metronomic chemotherapy, they may inhibit angiogenesis and induce immunity. In our previous study, we showed that low-dose gemcitabine caused telomere shortening by stabilizing TRF2 that was required for XPF-dependent telomere loss. In this report, we established a SKOV3.ip1 ascites cell model. Tumor-bearing mice were treated with low-dose gemcitabine (GEM) or capecitabine (CAP). Both GEM and CAP caused telomere shortening and increased expression of TRF2 with improved ascites in nude mice and decreased in vitro clonogenic activity. TRF2 knockdown altered telomeres to a shortened but new status that may evade XPF-dependent telomere loss and conferred resistance of SKOV3.ip1 ascites cells to low-dose GEM and CAP. Our study provides a new mechanism of metronomic chemotherapy i.e. TRF2 is required for metronomic therapeutic effects of gemcitabine and capecitabine.

Pilyugin M, André PA, Ratajska M, et al.
Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability.
Oncotarget. 2017; 8(6):9339-9353 [PubMed] Free Access to Full Article Related Publications
Previous reports have shown that expression of BARD1δ, a deletion-bearing isoform of BARD1, correlates with tumor aggressiveness and progression. We show that expression of BARD1δ induces cell cycle arrest in vitro and in vivo in non-malignant cells. We investigated the mechanism that leads to proliferation arrest and found that BARD1δ overexpression induced mitotic arrest with chromosome and telomere aberrations in cell cultures, in transgenic mice, and in cells from human breast and ovarian cancer patients with BARD1 mutations. BARD1δ binds more efficiently than BARD1 to telomere binding proteins and causes their depletion from telomeres, leading to telomere and chromosomal instability. While this induces cell cycle arrest, cancer cells lacking G2/M checkpoint controls might continue to proliferate despite the BARD1δ-induced chromosomal instability. These features of BARD1δ may make it a genome permutator and a driver of continuous uncontrolled proliferation of cancer cells.

Kim W, Ludlow AT, Min J, et al.
Regulation of the Human Telomerase Gene TERT by Telomere Position Effect-Over Long Distances (TPE-OLD): Implications for Aging and Cancer.
PLoS Biol. 2016; 14(12):e2000016 [PubMed] Free Access to Full Article Related Publications
Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.

Boer JM, Steeghs EM, Marchante JR, et al.
Tyrosine kinase fusion genes in pediatric BCR-ABL1-like acute lymphoblastic leukemia.
Oncotarget. 2017; 8(3):4618-4628 [PubMed] Free Access to Full Article Related Publications
Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p<0.01), and also higher, albeit not statistically significant, compared with the fusion-negative BCR-ABL1-like group. The 8-year cumulative incidence of relapse in the fusion-positive BCR-ABL1-like group (35%) was comparable with that in the fusion-negative BCR-ABL1-like group (35%), and worse than in the non-BCR-ABL1-like B-other group (17%, p=0.07). IKZF1 deletions, predominantly other than the dominant-negative isoform and full deletion, co-occurred with tyrosine kinase fusions. This study shows that tyrosine kinase fusion-positive cases are a high-risk subtype of BCP-ALL, which warrants further studies with specific kinase inhibitors to improve outcome.

Wu M, Lin Z, Li X, et al.
HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2.
Sci Rep. 2016; 6:36045 [PubMed] Free Access to Full Article Related Publications
The dysregulation of lncRNAs has increasingly been linked to many human diseases, especially in cancers. Our results demonstrate HULC, MALAT1 and TRF2 are highly expressed in human hepatocellular carcinoma tissues, and HULC plus MALAT1 overexpression drastically promotes the growth of liver cancer stem cells. Mechanistically, both HULC and MALAT1 overexpression enhanced RNA polII, P300, CREPT to load on the promoter region of telomere repeat-binding factor 2(TRF2), triggering the overexpression, phosphorylation and SUMOylation of TRF2. Strikingly, the excessive TRF2 interacts with HULC or MALAT1 to form the complex that loads on the telomeric region, replacing the CST/AAF and recruiting POT1, pPOT1, ExoI, SNM1B, HP1 α. Accordingly, the telomere is greatly protected and enlonged. Furthermore, the excessive HULC plus MALAT1 reduced the methylation of the TERC promoter dependent on TRF2, increasing the TERC expression that causes the increase of interplay between TRET and TERC. Ultimately, the interaction between RFC and PCNA or between CDK2 and CyclinE, the telomerase activity and the microsatellite instability (MSI) are significantly increased in the liver cancer stem cells. Our demonstrations suggest that haploinsufficiency of HULC/MALAT1 plays an important role in malignant growth of liver cancer stem cell.

Xu Y, Wang X, Chen SM, et al.
Effect of silencing key proteins in telomerase mechanism and alternative lengthening of telomeres mechanism in laryngeal cancer cells.
Am J Otolaryngol. 2016 Nov - Dec; 37(6):552-558 [PubMed] Related Publications
PURPOSE: To explore the influences of telomerase and alternative lengthening of telomeres mechanism on telomere length and laryngeal squamous cell carcinoma in vitro and in vivo.
MATERIALS AND METHODS: Short hairpin RNA expression vectors targeting the messenger TERT, TRF2, RAD51 and NBS1 were constructed. The mRNA and protein expression of targeted genes in human laryngeal squamous carcinoma cell line HEp-2 was evaluated by reverse transcription polymerase chain reaction and Western blotting separately. The length of telomere was analyzed by fluorescent in-situ hybridization. Cell viability was examined by cell counting Kit-8. Effects on tumor growth were also investigated in vivo.
RESULTS: The transfection of multiple short hairpin RNAs expression plasmid significantly inhibited the mRNA and protein expression of related genes. Silence of alternative lengthening of telomeres mechanism and telomerase mechanism related genes resulted in the shortening of telomere length in HEp-2 cell. However, silence of alternative lengthening of telomeres mechanism related genes could shorten the telomere length but had no significant difference. Both simultaneously and separately blocking telomerase mechanism and alternative lengthening of telomeres mechanism resulted in reduction of tumor cell viability. Silence of alternative lengthening of telomeres mechanism and telomerase mechanism related genes inhibited the tumor growth in vivo.
CONCLUSIONS: The inhibition of telomere related gene may be a promising strategy for the treatment of laryngeal squamous cell carcinoma.

An J, Wu M, Xin X, et al.
Inflammatory related gene IKKα, IKKβ, IKKγ cooperates to determine liver cancer stem cells progression by altering telomere via heterochromatin protein 1-HOTAIR axis.
Oncotarget. 2016; 7(31):50131-50149 [PubMed] Free Access to Full Article Related Publications
Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKKα, IKKβ, IKKγ. Herein, we demonstrate that IKKα plus IKKβ promoted and IKKγ inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKKα plus IKKβ enhanced and IKKγ inhibited the interplay among HP1α, HP1β and HP1γ that competes for the interaction among HP1α, SUZ12, HEZ2. Therefore, IKKα plus IKKβ inhibited and IKKγ enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region. Therefore, IKKα plus IKKβ increased and IKKγ decreased the HOTAIR expression. Strikingly, IKKα plus IKKβ decreases and IKKγ increases the HP1α interplays with DNA methyltransferase DNMT3b, which increases or decreases TERRA promoter DNA methylation. Thus IKKα plus IKKβ reduces and IKKγ increases to recruit TRF1 and RNA polymerase II deposition and elongation on the TERRA promoter locus, which increases or decreases TERRA expression. Furthermore, IKKα plus IKKβ decreases/increases and IKKγ increases/decreases the interplay between TERT and TRRRA/between TERT and TREC. Ultimately, IKKα plus IKKβ increases and IKKγ decreases the telomerase activity. On the other hand, at the telomere locus, IKKα plus IKKβ increases/drcreases and IKKγ decreases/increases TRF2, POT1, pPOT1, Exo1, pExo1, SNM1B, pSNM1B/CST-AAF binding, which keep active telomere regulatory genes and poised for telomere length. Strikingly, HOTAIR is required for IKKα plus IKKβ and IKKγ to control telomerase activity and telomere length. These observations suggest that HOTAIR operates the action of IKKα, IKKβ, IKKγ in liver cancer stem cells. This study provides a novel basis to elucidate the oncogenic action of IKKα, IKKβ, IKKγ and prompts that IKKα, IKKβ, IKKγ cooperate to HOTAR to be used as a novel therapeutic targets for liver cancer.

Benhamou Y, Picco V, Raybaud H, et al.
Telomeric repeat-binding factor 2: a marker for survival and anti-EGFR efficacy in oral carcinoma.
Oncotarget. 2016; 7(28):44236-44251 [PubMed] Free Access to Full Article Related Publications
Oral Squamous Cell Carcinoma (OSCC) is the most common oral cancer worldwide. Treatments including surgery, radio- and chemo-therapies mostly result in debilitating side effects. Thus, a more accurate evaluation of patients at risk of recurrence after radio/chemo treatment is important for preserving their quality of life. We assessed whether the Telomeric Repeat-binding Factor 2 (TERF2) influences tumor aggressiveness and treatment response. TERF2 is over-expressed in many cancers but its correlation to patient outcome remains controversial in OSCC. Our retrospective study on sixty-two patients showed that TERF2 overexpression has a negative impact on survival time. TERF2-dependent survival time was independent of tumor size in a multivariate analysis. In vitro, TERF2 knockdown by RNA interference had no effect on cell proliferation, migration, senescence and apoptosis. Instead, TERF2 knockdown increased the expression of cytokines implicated in inflammation and angiogenesis, except for vascular endothelial growth factor. TERF2 knockdown resulted in a decrease vascularization and growth of xenograft tumors. Finally, response to erlotinib/Tarceva and cetuximab/Erbitux treatment was increased in TRF2 knocked-down cells. Hence, TERF2 may represent an independent marker of survival for OSCC and a predictive marker for cetuximab/Erbitux and erlotinib/Tarceva efficacy.

Zheng S, Cherniack AD, Dewal N, et al.
Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma.
Cancer Cell. 2016; 29(5):723-736 [PubMed] Free Access to Full Article Related Publications
We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.

Long E, Ilie M, Bence C, et al.
High expression of TRF2, SOX10, and CD10 in circulating tumor microemboli detected in metastatic melanoma patients. A potential impact for the assessment of disease aggressiveness.
Cancer Med. 2016; 5(6):1022-30 [PubMed] Free Access to Full Article Related Publications
Circulating tumors cells (CTCs) can be detected in the blood of metastatic melanoma patients (MMPs) both as isolated circulating tumor cells (iCTCs) and circulating tumor microemboli (CTMs), but their clinical significance remains unknown. The aim of this work was to evaluate the prognostic impact in metastatic cutaneous melanoma of CTMs and iCTCs identified by a cytomorphological approach using the isolation by size of tumor cell (ISET) method. We characterized the phenotype of CTCs using anti-PS100, anti-SOX10, anti-CD10, and anti-TRF2 antibodies. 128 MMPs and 37 control healthy individuals with benign nevi were included in this study. Results were compared to the follow-up of patients. 109/128 (85%) MMPs showed CTCs, 44/128 (34%) with 2 to 6 CTMs and 65/128 (51%) with 4 to 9 iCTCs. PS100 expression was homogeneous in iCTCs and heterogeneous in CTMs. SOX10, CD10, and TRF2 were mainly expressed in CTMs. None of the control subjects demonstrated circulating malignant tumor cells. Overall survival was significantly decreased in patients with CTMs, independently of the therapeutic strategies. In conclusion, the presence of CTMs is an independent predictor of shorter survival from the time of diagnosis of MMPs.

Kibel AS, Ahn J, Isikbay M, et al.
Genetic variants in cell cycle control pathway confer susceptibility to aggressive prostate carcinoma.
Prostate. 2016; 76(5):479-90 [PubMed] Related Publications
BACKGROUND: Because a significant number of patients with prostate cancer (PCa) are diagnosed with disease unlikely to cause harm, genetic markers associated with clinically aggressive PCa have potential clinical utility. Since cell cycle checkpoint dysregulation is crucial for the development and progression of cancer, we tested the hypothesis that common germ-line variants within cell cycle genes were associated with aggressive PCa.
METHODS: Via a two-stage design, 364 common sequence variants in 88 genes were tested. The initial stage consisted of 258 aggressive PCa patients and 442 controls, and the second stage added 384 aggressive PCa Patients and 463 controls. European-American and African-American samples were analyzed separately. In the first stage, SNPs were typed by Illumina Goldengate assay while in the second stage SNPs were typed by Pyrosequencing assays. Genotype frequencies between cases and controls were compared using logistical regression analysis with additive, dominant and recessive models.
RESULTS: Eleven variants within 10 genes (CCNC, CCND3, CCNG1, CCNT2, CDK6, MDM2, SKP2, WEE1, YWHAB, YWHAH) in the European-American population and nine variants in 7 genes (CCNG1, CDK2, CDK5, MDM2, RB1, SMAD3, TERF2) in the African-American population were found to be associated with aggressive PCa using at least one model. Of particular interest, CCNC (rs3380812) was associated with risk in European-American cohorts from both institutions. CDK2 (rs1045435) and CDK5 (rs2069459) were associated with risk in the African-American cohorts from both institutions. Lastly, variants within MDM2 and CCNG1 were protective for aggressive PCa in both ethnic groups.
CONCLUSIONS: This study confirms that polymorphisms within cell cycle genes are associated with clinically aggressive PCa. Validation of these markers in additional populations is necessary, but these markers may help identify patients at risk for potentially lethal carcinoma.

Nera B, Huang HS, Lai T, Xu L
Elevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions.
Nat Commun. 2015; 6:10132 [PubMed] Free Access to Full Article Related Publications
The shelterin protein TRF2 is essential for chromosome-end protection. Depletion of TRF2 causes chromosome end-to-end fusions, initiating genomic instability that can be cancer promoting. Paradoxically, significant increased levels of TRF2 are observed in a subset of human cancers. Experimental overexpression of TRF2 has also been shown to induce telomere shortening, through an unknown mechanism. Here we report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), ultimately leading to stochastic loss of telomeric sequences. These TRF2 overexpression-induced telomere deletions generate chromosome fusions resembling those detected in human cancers and in mammalian cells containing critically shortened telomeres. Therefore, our findings have uncovered a second pathway by which altered TRF2 protein levels can induce end-to-end fusions. The observations also provide mechanistic insight into the molecular basis of genomic instability in tumour cells containing significantly increased TRF2 levels.

Li T, Zheng Q, An J, et al.
SET1A Cooperates With CUDR to Promote Liver Cancer Growth and Hepatocyte-like Stem Cell Malignant Transformation Epigenetically.
Mol Ther. 2016; 24(2):261-275 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNA CUDR plays an important role during tumorigenesis. Herein, we demonstrate that SET1A cooperates with CUDR to accelerate hepatocarcinogenesis and promote malignant transformation of hepatocyte-like stem cells. Mechanistically, CUDR enhances the phosphorylation of RB1, C-myc expression, and the interplay between the SET1A and pRB1. Notably, CUDR acts as a sponge cushion that shows a link between SET1A and pRB1, producing a activated pRB1-SET1A complex. On the other hand, the pRB1-SET1A complex may carry methyls(me) to occupy the position of H3K4, resulting in specific tri-methylation of forth lysine of histone H3 (H3K4me3). Thereby, the H3K4me3 loads on the TRF2 promoter region which causes the TRF2 overexpression. Ultimately, the excessive TRF2 binds to telomere repeat DNA, prolonging the telomere length. These findings provide the first demonstration that SET1A cooperates with CUDR to play a positive potential role during hepatocarcinogenesis and hepatocyte-like stem cells' malignant transformation epigenetically.

Hayashi MT, Cesare AJ, Rivera T, Karlseder J
Cell death during crisis is mediated by mitotic telomere deprotection.
Nature. 2015; 522(7557):492-6 [PubMed] Free Access to Full Article Related Publications
Tumour formation is blocked by two barriers: replicative senescence and crisis. Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. This phenotype is induced by loss of p53 function, and is suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating that such fusions are the underlying cause of cell death. Exacerbation of mitotic telomere deprotection by partial TRF2 (also known as TERF2) knockdown increased the ratio of cells that died during mitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherein chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population.

Manandhar M, Boulware KS, Wood RD
The ERCC1 and ERCC4 (XPF) genes and gene products.
Gene. 2015; 569(2):153-61 [PubMed] Free Access to Full Article Related Publications
The ERCC1 and ERCC4 genes encode the two subunits of the ERCC1-XPF nuclease. This enzyme plays an important role in repair of DNA damage and in maintaining genomic stability. ERCC1-XPF nuclease nicks DNA specifically at junctions between double-stranded and single-stranded DNA, when the single-strand is oriented 5' to 3' away from a junction. ERCC1-XPF is a core component of nucleotide excision repair and also plays a role in interstrand crosslink repair, some pathways of double-strand break repair by homologous recombination and end-joining, as a backup enzyme in base excision repair, and in telomere length regulation. In many of these activities, ERCC1-XPF complex cleaves the 3' tails of DNA intermediates in preparation for further processing. ERCC1-XPF interacts with other proteins including XPA, RPA, SLX4 and TRF2 to perform its functions. Disruption of these interactions or direct targeting of ERCC1-XPF to decrease its DNA repair function might be a useful strategy to increase the sensitivity of cancer cells to some DNA damaging agents. Complete deletion of either ERCC1 or ERCC4 is not compatible with viability in mice or humans. However, mutations in the ERCC1 or ERCC4 genes cause a remarkable array of rare inherited human disorders. These include specific forms of xeroderma pigmentosum, Cockayne syndrome, Fanconi anemia, XFE progeria and cerebro-oculo-facio-skeletal syndrome.

Gurung RL, Lim SN, Low GK, Hande MP
MST-312 Alters Telomere Dynamics, Gene Expression Profiles and Growth in Human Breast Cancer Cells.
J Nutrigenet Nutrigenomics. 2014; 7(4-6):283-98 [PubMed] Related Publications
BACKGROUND: Targeting telomerase is a potential cancer management strategy given that it allows unlimited cellular replication in the majority of cancers. Dysfunctional telomeres are recognized as double-strand breaks. However, the status of DNA repair response pathways following telomerase inhibition is not well understood in human breast cancer cells. Here, we evaluated the effects of MST-312, a chemically modified derivative from tea catechin, epigallocatechin gallate, on telomere dynamics and DNA damage gene expression in breast cancer cells.
METHODOLOGY: Breast cancer cells MCF-7 and MDA-MB-231 were treated with MST-312, and telomere-telomerase homeostasis, induced DNA damage and gene expression profiling were analyzed.
RESULTS: MST-312 decreased telomerase activity and induced telomere dysfunction and growth arrest in breast cancer cells with more profound effects in MDA-MB-231 than in MCF-7 cells. Consistent with these data, the telomere-protective protein TRF2 was downregulated in MDA-MB-231 cells. MST-312 induced DNA damage at telomeres accompanied by reduced expression of DNA damage-related genes ATM and RAD50. Co-treatment with MST-312 and the poly(ADP-ribose) polymerase 1 (PARP-1) inhibitor PJ-34 further enhanced growth reduction as compared to single treatment with MST-312 or PJ-34.
CONCLUSIONS: Our work demonstrates potential importance for the establishment of antitelomerase cancer therapy using MST-312 along with PARP-1 inhibition in breast cancer therapy.

Saha A, Shree Padhi S, Roy S, Banerjee B
HCT116 colonospheres shows elevated expression of hTERT and β-catenin protein - a short report.
J Stem Cells. 2014; 9(4):243-51 [PubMed] Related Publications
AIM: Clonospheres formed due to modified culture conditions are often studied for their stem cell like behaviour. The main objective of the current study is to compare the stem cell markers and link it to hTERT levels by monitoring their quantitative gene expression as they are potential targets for new generation combination therapeutics.
METHOD: In the present study we created stable colonospheres of Human colon cancer cell line HCT-116 long term culture conditions of Serum deprivation. Clonospheres formed after 15 days were collected by gentle and enzymatic dissociation was performed. Single cell suspension was obtained by mechanically dissociating the cells through a 22G needle. Single cells were replanted at a density 1200 cells/ml in Serum Free Medium in the 6 well plates for further passage. Passaging of cells was done at an interval of 8 days. The spheres formed were cyto-spun in special slides for Immunocytochemistry (ICC) studies for β-catenin protein and hTERT. The colonospheres were also processed for real time PCR expression studies for the same genes to confirm.
RESULTS: In this present study, immunofluorescence studies revealed high β-catenin expression in the nucleus in colonospheres as compared to that of differentiated cancer cell line HCT-116 where the signal was localized mostly in the membranous and non-nuclear regions. Also increased TRF2 signal in colonospheres indicated higher activity of hTERT gene as TRF2 is the direct activator of hTERT to protect the telomere. Quantitative PCR studies showed that there was a significant over expression (p<0.05) at the mRNA level of the hTERT, TRF2, Rap1 genes along with the β-catenin over expression. Immunofluorescence analysis also revealed higher expression of CSC marker CD44 and ALDH1in colonospheres compared to the parental population.
CONCLUSION: Clonospheres sub-population is showing higher degree of hTERT gene expression along with β-catenin when compared to the parental HCT-116 cancer cells. We also checked the co expression of other telomere maintenance genes mainly TRF 2 and Rap1 which also showed similar results. Therefore, we conclude that not only hTERT but possibly other Sheltrin proteins are regulated by β-catenin which is co expressed.

Pal D, Sharma U, Singh SK, et al.
Over-expression of telomere binding factors (TRF1 & TRF2) in renal cell carcinoma and their inhibition by using SiRNA induce apoptosis, reduce cell proliferation and migration invitro.
PLoS One. 2015; 10(3):e0115651 [PubMed] Free Access to Full Article Related Publications
Telomere binding factors viz. TRF1 and TRF2 are a part of sheltrin complex that are present exclusively at the ends of chromosomes. These factors play an important role in maintaining chromosomal integrity at the ends. However, their status and role are not clear in renal cell carcinoma (RCC). Therefore, the present study was conducted to evaluate TRF1 and TRF2 expressions in RCC tissues. Further, the role of these factors involved in tumorigenesis was elucidated by gene silencing using siRNA in RCC cell line (A498). The present study documented a significant over-expression of TRF1 (P = 0.005) and TRF2 (P = 0.0048) mRNAs by real time PCR in RCC tissues as compared with adjacent normal kidney tissues. Immunohistochemistry studies also revealed higher expression of TRF1 and TRF2 proteins in RCC. Moreover, TRF1 or TRF2 gene silencing using siRNA showed marked reduction in proliferation of RCC cells (P = 0.000). Further, significantly induced cell cycle arrest (P = 0.000) and apoptosis of RCC cells (P = 0.000) was documented upon TRF1 or TRF2 gene silencing. Henceforth, the results deduce that TRF1 or TRF2 inhibitions play an important role in the induction of apoptosis in A498 cells, which may serve as a potential therapeutic target in RCC.

Marzec P, Armenise C, Pérot G, et al.
Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers.
Cell. 2015; 160(5):913-927 [PubMed] Related Publications
The breakage-fusion-bridge cycle is a classical mechanism of telomere-driven genome instability in which dysfunctional telomeres are fused to other chromosomal extremities, creating dicentric chromosomes that eventually break at mitosis. Here, we uncover a distinct pathway of telomere-driven genome instability, specifically occurring in cells that maintain telomeres with the alternative lengthening of telomeres mechanism. We show that, in these cells, telomeric DNA is added to multiple discrete sites throughout the genome, corresponding to regions regulated by NR2C/F transcription factors. These proteins drive local telomere DNA addition by recruiting telomeric chromatin. This mechanism, which we name targeted telomere insertion (TTI), generates potential common fragile sites that destabilize the genome. We propose that TTI driven by NR2C/F proteins contributes to the formation of complex karyotypes in ALT tumors.

Ozden S, Tiber PM, Ozgen Z, et al.
Expression of TRF2 and its prognostic relevance in advanced stage cervical cancer patients.
Biol Res. 2014; 47:61 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Telomeres are protective caps consisted of specific tandem repeats (5'-TTAGGG-3'). Shortening of telomeres at each cell division is known as "mitotic clock" of the cells, which renders telomeres as important regulators of lifespan. TRF2 is one of the critical members of shelterin complex, which is a protein complex responsible from the preservation of cap structure, and loss or mutation of TRF2 results in DNA damage, senescence or apoptosis. Since cancer is frequently associated with aberrant cell cycle progression, defective DNA repair or apoptosis pathways, TRF2 could be one likely candidate for cancer therapy. Here we investigated the prognostic role of TRF2 levels in cervical cancer patients. Fold-induction rates were evaluated with respect to median values after real-time PCR analysis. Overall survival, distant disease-free and local recurrence-free survival rates were calculated using Kaplan-Meier long rank test.
RESULTS: Both five year overall- and disease-free survival rates were longer in patients with higher TRF2 expression compared to lower expression, but results were not statistically significant (69.2% vs 28.9%, respectively). Mean local recurrence-free survivals (LRF) were very close ( 58.6, CI: 44.3-72.9 vs 54.5, CI: 32.1-76.9 months) for high and low expressions, respectively. Cumulative proportion of LRF at the end of five year period was 76.9% for high and 57.1% for low TRF2 expression (P = 0.75). Statistically significant difference was found between survival ratios and Bcl-xL and p53 gene expressions, but not with TRF2. A respectable correlation between TRF2 expression and apoptosis along with distant metastasis was noted (P = 0.045 and 0.036, respectively). Additionally, high TRF2 expression levels had a positive impact in five year survival rate of stage IIIB-IVA patients (P = 0.04).
CONCLUSIONS: Our results support the role of TRF2 in apoptosis and imply a positive relation with distant metastases and survival in advanced stage patients. The remarkable difference in survival periods of patients with different TRF2 expressions suggest that TRF2 may be a candidate factor to estimate survival for cervical cancer, a preliminary observation which should further be verified with a larger cohort.

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