Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players
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,...
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| Vydáno v: | Oncogene Ročník 38; číslo 34; s. 6172 - 6183 |
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| Hlavní autoři: | , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
London
Nature Publishing Group UK
01.08.2019
Nature Publishing Group |
| Témata: | |
| ISSN: | 0950-9232, 1476-5594, 1476-5594 |
| On-line přístup: | Získat plný text |
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| Shrnutí: | 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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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Literature Review-3 ObjectType-Review-3 content type line 23 |
| ISSN: | 0950-9232 1476-5594 1476-5594 |
| DOI: | 10.1038/s41388-019-0872-9 |