TERT—Regulation and Roles in Cancer Formation

Abstract

Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex TERT changes such as gene amplifications, TERT structural variants, TERT promoter germline and somatic mutations, TERT epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level. TERT expression is regulated in tumors via multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity via TERT expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of TERT in different mechanisms of cancer development and regulation.

Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis

“…These mutations result in a new consensus binding site for E-twenty-six (ETS) transcription factors and this may contribute to increased TERT . The ETS transcription factors are downstream targets of the RAS-RAF-MAPK pathways, and TERT promoter mutations are suggested to have synergistic effects with activating BRAF or NRAS mutations to promote tumor cell proliferation [ 21 ]. TERT is involved in the AKT pathway, and plays an important role in cellular immortality [ 6 ].…”

“…TERT mRNA overexpression does not completely explain all effects of the TERT promoter mutations in tumorigenesis, and the role of immunohistochemistry in determining the TERT status is still a topic of debate [ 22 ]. Consequently, other undefined or epigenetic mechanisms of TERT -upregulating are expected to exist [ 21 , 23 , 24 ]. While a TERT promoter mutation is not found in conjunctival nevi, it is found in both PAM [ 14 ] and CM [ 6 , 14 ], with increased TERT expression leading to tumor progression [ 6 ].…”

Hypoxia-Driven HIF-1α Activation Reprograms Pre-Activated NK Cells towards Highly Potent Effector Phenotypes via ERK/STAT3 Pathways

“…Our study also demonstrated STAT3 activation by hypoxia to be essential for the acquisition of survival and functional benefits of NK cells. STAT3 is known to be an activator of human telomerase reverse transcriptase (hTERT) [ 45 ], and NK cell senescence from mbIL15-mediated expansion can be restored with hTERT gene modification. Since our data showed a reduction in the expression of p21/p53 tumor suppressors [ 46 ], along with a concomitant decrease in p16 mRNAs (data not shown) in hypoxia-exposed NK cells, inhibition of senescence by promoting hTERT activity could also have contributed to the increase in NK cells beyond 20 days of ex-vivo hypoxic NK culture.…”

Mutant MEG3 Enhances the Activity of Telomerase by Increasing DNA Damage Repair in Human Liver Cancer Stem Cells

“…Furthermore, our results indicate that TERT determines the cancerous function of mutant MEG3. Telomerase, an RNA-dependent DNA polymerase with telomerase reverse transcriptase (TERT), regulates cancer formation (54,55).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 β-Catenin(56). TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma (57).DNA methylation of the TERT promoter is associated with human cancer(58).TERT and TERC mutations suppress telomerase activity (59).TERT C228T mutation is associated with intravesical recurrence for patients with non-muscle invasive bladder cancer(60).TERC is an RNA component of telomerase and TERC promotes cellular in ammatory response independent of telomerase(61).…”