Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: Old actors and new players
Open accessAbstract
Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.
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TERT acts as a rate-limiter of telomerase activity.
“it is well established that due to its suppression, TERT acts as a rate-limiter of telomerase activity [177].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [177]
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Self-citationHuman Telomerase Reverse Transcriptase (hTERT) Positively Regulates 26S Proteasome Activity
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Telomerase Reverse Transcriptase Regulates microRNAs
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RETRACTED: New intranasal and injectable gene therapy for healthy life extension
Jaijyan, D. K., Selariu, A., Cruz-Cosme, R., Tong, M., Yang, S., Stefa, A., Kekich, D., Sadoshima, J., Herbig, U., Tang, Q., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2121499119 · Cited by 57 · see citing works
RetractedCurrent and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy
Nikolouzakis, T. K., Chrysos, E., Docea, A. O., Fragkiadaki, P., Souglakos, J., Tsiaoussis, J., & Tsatsakis, A. (2024) · Cancers · doi:10.3390/cancers16111995 · Cited by 37 · see citing works
- Authors
- Yuan, X., Larsson, C., & Xu, D.
- Affiliations
- Karolinska University Hospital (SE)
- Corresponding author
- Yuan, Xiaotian
- Xu, Dawei
- Venue
- Oncogene
- Published
- 2019-07-08
- Volume
- 38
- Issue
- 34
- Pages
- 6172-6183
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC6756069
- OpenAlex
- W2962043899
- Cited by
- 450
- References
- 101
- Citations by year
- 2026: 26 · 2025: 64 · 2024: 67 · 2023: 55 · 2022: 72 · 2021: 81 · 2020: 77 · 2019: 7 · 2018: 1
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Oncogene (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Swedish Foundation for International Cooperation in Research and Higher Education
- Cancerfonden
- China Postdoctoral Science Foundation (2019M652404)
- Karolinska Institutet
- Vetenskapsrådet
- Cancerföreningen i Stockholm
- Ruth och Richard Julins Stiftelse
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- telomerase reverse transcriptase, telomerase activation, TERT promoter mutation, gene amplification, telomere length, replicative senescence, cell immortalization, oncogenic signaling, tumor progression, cancer genomics
- MeSH terms
- Cell Transformation, Neoplastic, Humans, Mutation, Neoplasms, Promoter Regions, Genetic, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Telomere, Disease Progression, Telomerase, Telomere Homeostasis, Telomere Shortening
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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