Telomeres, telomerase, and cancer: mechanisms, biomarkers, and therapeutics

Abstract

Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy.

Keywords: Cancer; Telomere shortening; Telomeres.

Fig. 1

Telomerase and Its Role in Cancer Progression. Telomerase enables the immortalization of cancer cells, while also promoting their proliferation, metastasis, invasion, and immune evasion. Additionally, it facilitates angiogenesis, regulates metabolic processes, and safeguards cancer cells from growth inhibition and death

Fig. 2

The Structure of Telomeres and Telomerase. A Structure of Telomeres and Shelterin complex. POT1, protection of telomeres 1. RAP1, repressor/activator protein 1. TIN2, TERF1-interacting nuclear factor 2. TPP1, telomere protection protein 1. TRF1, telomeric repeat binding factor 1. TRF2, telomeric repeat binding factor 2. B Structure of Telomerase holoenzyme. TEN, Telomerase Essential N-terminal. TRBD, Telomerase RNA Binding Domain; RT, reverse transcriptase domain and CTE, C-Terminal Extension domain. PK/T, pseudoknot/template. CR4/5, conserved regions 4 and 5. GAR1, nucleolar protein family A. member 1. NHP2, nucleolar protein family A, member 2. NOP10, nucleolar protein 10. TCAB1, telomerase Cajal body protein 1. H2A, Histone 2A. H2B, Histone 2B. TERT and the H2A-H2B dimer constitute the catalytic core in conjunction with the PK/T and CR4/5. The remaining subunits interact with the H/ACA domain, forming the H/ACA lobe. Box H, Hairpin Box. ACA, “ACA” Box. TMG, Trimethylguanosine Cap.

Fig. 3

Telomere Shortening and Cellular Checkpoints. Under the influence of aging and disease-related factors, telomere shortening results in an increase in chromosomal instability. If the telomere checkpoint remains functional, cells will cease further replication once telomeres reach a critical length. When DNA damage checkpoints are intact, single-strand or double-strand breaks occurring during replication activate repair mechanisms, including the ATM and ATR signaling pathways. These pathways exert their effects by inhibiting the activity of the Cyclin/CDK complexes, thereby halting cell cycle progression and allowing sufficient time for DNA repair. Should repair fail, the cell will undergo either senescence or apoptosis. However, in cases where checkpoint mechanisms are impaired, cells are unable to exit the cell cycle, leading to further telomere shortening and gradual accumulation of chromosomal abnormalities. During this process, chromosomal damage or fusion events may trigger cell death. If cell cycle checkpoints are inactivated and tumor suppressor genes such as p53 are compromised, abnormal cell division may occur, thereby increasing the likelihood of tetraploidy and exacerbating chromosomal instability. At this juncture, activation of telomerase bypasses the restrictions imposed by aging and cell death, enabling the accumulation of mutations within the immortalized cell, which eventually evolves into malignant tumor cells.

Fig. 4

Mechanisms of telomerase activation and TERT-driven cancer progression. A Telomerase activation through TERT expression occurs via four primary mechanisms: enhancer insertion, promoter methylation, chromosomal abnormalities, and promoter mutations. The insertion of enhancers and methylation of the promoter region alleviate the suppression of the TERT promoter, thereby initiating its expression. Chromosomal abnormalities, often resulting from mutations in genes such as APC, lead to the accumulation of JunD, which relaxes the chromatin structure. This facilitates long-range chromatin interactions mediated by Sp1, driving the activation of the TERT promoter and subsequent TERT expression. Promoter mutations involve alterations in the promoter region across various cancers, where specific mutation sites interact with distinct complexes to ultimately drive TERT expression. B, TERT can exert numerous functions beyond telomere maintenance within the cell, and through these functions, it facilitates the initiation and progression of cancer. As depicted in the figure, the activation of NF-κB, NRF2, and MYC (represented in blue) can, in turn, promote the expression of TERT.