<i>TERT</i>
            promoter mutations and telomerase reactivation in urothelial cancer

Borah, Sumit; Xi, Linghe; Zaug, Arthur J.; Powell, Natasha M.; Dancik, Garrett M.; Cohen, Scott B.; Costello, James C.; Theodorescu, Dan; Cech, Thomas R.

doi:10.1126/science.1260200

Cited by 278 publications

(274 citation statements)

References 31 publications

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“…[45][46][47] It appears that the level of telomerase activity is the best indicator of patient prognosis. 91 In an attempt to rationalize the molecular basis for the transcriptional effects of these somatic mutations of hTERT, it was first proposed that new ETS transcription factor binding sites are generated in the duplex form of the promoter. 45 More recently it has been proposed that GABP transcription factors can be recruited to mutant promoter elements in glioblastoma multiforme, 52 thus providing an additional mechanism for the effects of these mutations.…”

Section: Discussionmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wildtype (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing.We show that promoter mutations exert a detrimental effect on the folding of one of these Gquadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression effects cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and inducing senescence by decreasing telomerase activity and telomere length.We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.3

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Section: Discussionmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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“…In the latter process, TERT is required to stabilize the binding of MYC to its target gene promoters, thus affecting MYC-dependent transcriptional programs and oncogenic properties (51). It has also been recently reported that elevated TERT mRNA levels correlates with reduced disease-specific survival in urothelial carcinoma patients (22). In support of our in vitro study, we found clinical relevance in patient samples by which a significant inverse correlation was observed between ARID1A and TERT mRNA expression in ovarian clear cell carcinoma tissues.…”

Section: Discussionmentioning

confidence: 99%

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

Rahmanto¹,

Jung²,

et al. 2016

Journal of Biological Chemistry

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ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres. ARID1A3 encodes BAF250 (also known as p270), which interacts with the ATPase subunit, BRG1 or BRM, and a set of core subunits (BAF47, BAF155, and BAF170) to form the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. By utilizing the energy from ATP hydrolysis, these complexes rearrange the distribution of nucleosomes, thereby modifying chromatin configuration and DNA accessibility to cellular machineries involved in transcription, DNA replication, DNA methylation, and DNA repair (1-3).The discovery of molecular genetic aberrations in chromatin remodelers converged genetic and epigenetic dysregulation, which contributes to the development and progression of numerous diseases, including cancer. Somatic ARID1A mutations were first discovered in ovarian clear cell carcinoma (4, 5) and subsequently reported in endometrium-derived carcinomas and several other cancer types (6, 7). Mutations of ARID1A occur throughout the entire coding sequence, mostly frameshift and nonsense mutations, thereby resulting in a loss of ARID1A protein expression. Hence, ARID1A is implicated as a tumor suppressor, and indeed, functional studies have demonstrated that ARID1A loss can promote tumorigenesis by affecting proliferation, differentiation, and apoptosis (8 -10). At the molecular level, our previous study demonstrated that the ARID1A complex interacted and collaborated with p53 to regulate transcription of several effectors including CDKN1A encoding p21 (8). In genetically engineered mice, whereas Arid1a deletion by itself is insufficient to transform cells, codeletion of Arid1a with either Pten or Pik3ca is required to drive the formation of ovarian endometrioid and clear cell-like carcinomas, respectively (11, 12).To further elucidate molecular mechanisms of ARID1A in preventing tumorigenesis, we sought to identify additional molecular genetic alterations that tend to be absent in ARID1A mutated tumors. The nature of ...

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“…In a study using 23 urothelial cancer cell lines, Borah and coworkers confirmed that TERT promoter mutations correlate with higher levels of TERT mRNA, TERT protein, telomerase enzymatic activity and telomere length (Borah et al 2015). Furthermore, TERT promoter mutations also correlate with worse patient outcome and reduced disease-specific survival in two independent patient cohorts (Borah et al 2015).…”

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 95%

“…Furthermore, TERT promoter mutations also correlate with worse patient outcome and reduced disease-specific survival in two independent patient cohorts (Borah et al 2015).…”

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 97%

“…As result of such, it would be interesting to understand how such mutations contribute through telomerase activity towards an immortalisation role. The main effects of TERT promoter mutations are summarised in Table 3. Using the new tool, CRISPR/Cas9, to study the recurrent mutations in the TERT promoter, Xi and coworkers (Xi et al 2015) verified that reverting the −124C > T mutation in a urothelial cancer cell line leads to decreased telomerase levels, telomere shortening and reduced proliferation rate (Xi et al 2015). These results suggest the causality of the mutation for telomerase activity, telomere length maintenance and cell growth rate (Xi et al 2015).…”

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 99%

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TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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TERT promoter mutations and telomerase reactivation in urothelial cancer

Cited by 278 publications

References 31 publications

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

TERT biology and function in cancer: beyond immortalisation

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