Mutation of the <i>TERT</i> promoter, switch to active chromatin, and monoallelic <i>TERT</i> expression in multiple cancers

Stern, Josh Lewis; Theodorescu, Dan; Vogelstein, Bert; Papadopoulos, Nickolas; Cech, Thomas R.

doi:10.1101/gad.269498.115

Cited by 178 publications

(203 citation statements)

References 39 publications

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“…Therefore, loss of ARID1A, which frequently occurs in endometrium-related and other carcinomas, may induce an open euchromatin configuration, allowing the transcription of TERT to start. In support of the above observations, a recent study demonstrated that mutation in TERT promoter can epigenetically switch chromatin into an active mode (24). Furthermore, Wu et al (47) demonstrated the ability of BRG1, the catalytic core subunit of the SWI/SNF chromatin remodel-FIGURE 3.…”

Section: Discussionmentioning

confidence: 54%

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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Section: Discussionmentioning

confidence: 54%

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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“…Recently discovered hTERT promoter mutations have been shown to promote telomerase expression by creating additional consensus binding sites for ETS family transcription factors and by triggering an epigenetic switch from inactive to active chromatin at the hTERT promoter (25,26,44). Most cancers, however, reactivate telomerase expression by mechanisms that are independent of promoter mutations.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, cancer cells display a pattern of active chromatin marks surrounding the hTERT promoter, thereby allowing transcription factors such as c-Myc to promote expression of the hTERT gene (24). Recently discovered hTERT promoter mutations in human cancer cells have been demonstrated to alter the local epigenetic landscape from a repressive state to open and transcriptionally active chromatin, providing a mechanism that may act as an epigenetic switch at the hTERT promoter (25). However, because most cancers reactivate hTERT gene expression independent of promoter mutations (26), other and currently unknown mechanisms must exist that promote epigenetic changes and create an active chromatin state at the hTERT promoter during cancer development in humans.…”

Section: Significancementioning

confidence: 99%

Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

Patel

Anitha

Mirani

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

121

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Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc-dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.oncogene-induced senescence | telomerase | telomere | senescence escape |

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“…34,39 Functionally, as shown in multiple cell lines, the 2124C>T TERT promoter mutation causes an epigenetic switch from an inactive to active chromatin mark leading to recruitment of GABPA/B1 transcription factor at the site. 40 The 2146C>T mutation in the TERT promoter, on the other hand, has been shown to be driven by noncanonical NF-kB signaling. 41 Incidentally, in melanoma both 2124C>T and 2146C>T mutations occur at almost similar frequencies; in all other malignancies the former mutation is overwhelmingly predominant.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

TERT promoter mutations in melanoma survival

Nagore

Heidenreich

Rachakonda

et al. 2016

Intl Journal of Cancer

107

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Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.Cutaneous melanoma represents one of the most aggressive skin cancers with its propensity to metastasize and intrinsic resistance to treatment. 1 A majority of melanomas remain localized; however, in a proportion of patients, the tumors metastasize to local and distant organs with dismal outcomes.The refractoriness to treatment of patients with metastasized melanoma has been the main cause of the deaths associated with the disease. 2 Despite increased possibilities, with range of treatments including targeted and immunotherapies, of eliciting stable responses in patients with metastatic melanoma, the long-term prospectus in terms of treatment response is confined to disease management. 3 The identification of patients at risk of developing advanced disease at an early stage through use of somatic mutations as molecular biomarkers remains a valid medical issue.The melanoma genome is characterized by one of the highest prevalence of somatic mutations, and the mutational pattern depicts characteristic ultraviolet signature. 4 Besides recurrent mutations in TERT promoter, BRAF/NRAS, CDKN2A, NF1, PTEN and others genes, various sequencing initiatives have identified mutations in a number of other genes including GRIN2A, RAC1, BCL2L12, STK19, FBXW7 and RPS27. [5][6][7][8][9][10][11][12][13][14] The mutations in the promoter of TERT gene, mainly at 2124 (...

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Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers

Cited by 178 publications

References 39 publications

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

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

Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

TERT promoter mutations in melanoma survival

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