Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity

Koh, Cheryl M.; Khattar, Ekta; Leow, Shi Chi; Liu, Chia Yi; Müller, Julius; Ang, Wei Xia; Li, Yinghui; Franzoso, Guido; Li, Shang; Guccione, Ernesto; Tergaonkar, Vinay

doi:10.1172/jci79134

Cited by 137 publications

(124 citation statements)

References 77 publications

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“…We analyzed breast and liver cancer samples for expression levels of TERT and pre-tRNA transcripts. Breast cancer samples were subdivided into ulates MYC-dependent transcription in lymphomas (40). In accordance with this, we found that in P493 cells (highly MYC driven), 20% of the target genes bound by TERT are also direct MYC targets (73,74), indicating that TERT might be binding to these regions through MYC.…”

Section: Loss Of Tert Is Associated With Reduced Pymt-initiated Mammasupporting

confidence: 73%

“…The EIF2A promoter was used as a positive control for RNA polymerase II (pol II) binding and as a negative control for pol III binding (Supplemental Figure 4, A and B). We recently reported that TERT interacts with MYC, thus stabilizing its levels posttranslationally and regulating MYC-dependent transcription (40). Further, MYC is known to stimulate pol III activity (41).…”

Section: Resultsmentioning

confidence: 99%

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Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression

Khattar¹,

Kumar²,

Liu³

et al. 2016

Journal of Clinical Investigation

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109

103

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Section: Loss Of Tert Is Associated With Reduced Pymt-initiated Mammasupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression

Khattar¹,

Kumar²,

Liu³

et al. 2016

Journal of Clinical Investigation

Self Cite

109

103

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“…It has been recently reported that activation of TERT expression confers a survival advantage of neoplastic cells by both telomere-dependent and -independent mechanisms. 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).…”

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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“…TERT is responsible for stabilisation of c-MYC levels in chromatin, contributing to either activation or repression of its target genes. TERT regulates c-MYC ubiquitination and proteosomal degradation, independent of its telomeric role, suggesting a feedforward mechanism able to potentiate c-MYC-dependent oncogenesis (Koh et al 2015).…”

Section: Regulators and Targets Of Tert Within Major Signalling Pathwmentioning

confidence: 99%

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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Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity

Cited by 137 publications

References 77 publications

Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression

Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression

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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