Telomere-related Markers for Cancer

Abstract

Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far. To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and the identified mechanisms include the aberrant activation of telomerase or the alternative lengthening of telomere pathway responsible for telomere elongation, dysregulation and mutation of telomereassociated factors, and other telomere homeostasis-related signaling nodes. In the present review, these various strategies employed by malignant cells to regulate their telomere length, structure and function have been summarized, and potential implications of these findings in the rational development of telomere- based cancer therapy and other clinical applications for precision oncology have been discussed.

Keywords: Cancer therapy; Gene transcription; TERC; TERRA; TERT; TERT promoter mutation; Telomerase; Telomere..

Fig. (1)

The telomere structure/shelterin association and telomerase complex. (A) Telomeric DNA association with the shelterin complex. Telomeric DNA is 8 – 20 kb long double-stranded TTAGGG repeats with a shorter G-rich, single stranded overhang. The overhang invades into the duplexed region to form T-loops. The shelterin complex is composed of six different factors, including TRF1 (telomeric repeat-binding factor 1), TRF2 (telomeric repeat-binding factor 2), RAP1 (repressor and activator protein 1), TIN2 (TRF1-interacting nuclear protein 2), POT1 (protection of telomeres 1) and TPP1 (TINT1/PTOP/PIT1) or ACD (adrendocortical dysplasia homolog). They bind to either double- (TRF1, TRF2, RAP1 and TIN2) or single-stranded telomeric DNA (TPP1 and POT1). TRF2 and POT1 inhibit ataxia telangiectasia-mutated (ATM) Signaling/Non-homologous End Joining (NHEJ) and Rad3-related (ATR) signaling, respectively, thereby preventing DNA damage response. TPP1/POT1 regulates telomerase accessibility to telomeres for telomeric DNA synthesis in telomerase-proficient cells. TERRA interacts with TRF1/2 and other factors associated with telomere chromatin, and it is required for the maintenance of normal telomere structure and function. (B) The schematic of the telomerase complex. TERT and TERC are the core of the enzyme and other components include dyskerin, NOP10, NHP2, GAR, repotin (RP), pontin (Pp), heat shock proteins (hsp) 90 and 23.

Fig. (2)

The mechanism underlying shorter but stabilized telomeres in human cancer. (A) Telomere dynamics during cellular proliferation, senescence, crisis and malignant transformation. Normal human somatic cells lose their telomeric DNA progressively with each round of cell divisions and critical short telomeres trigger senescence if the checkpoint signaling (TP53 and pRB) is intact. However, their inactivation induces cells to bypass the senescence barrier and to continue proliferation until the M2 crisis stage where genomic catastrophes occur. Most cells undergo apoptosis, while rare cells survive and acquire immortal phenotype through telomerase activation. The presence of telomerase activity stabilizes cell telomeres at a short balance even after their transformation. Under rare circumstances, the alternative lengthening of telomere (ALT) pathway may be activated and the cells have heterogeneous telomere length (Shown as different lengths of orange lines). (B) The ALT activation induces longer telomere in cervical tumors. The CIN and invasive cancer samples from the same patient are analyzed for telomere length using FISH. Telomere signals (length) are very weak in CIN, but became significantly stronger in fully transformed tumor derived from that same patient. The patient was confirmed with ALT in her tumor. (C) Significantly telomere shortening occurs already in precursors during the carcinogenesis of uterine cervix. Telomere length assessment using quantitative fluorescence in situ hybridization (Q-FISH) shows that telomere length (green signals) is comparable between normal cervical epithelial (EP) and stromal cells, but greatly reduced telomere signals are seen at CIN2 and 3, and telomerase-positive invasive cancer cells as well. Telomere shortening is coupled with the activation of DNA damage response and increased proliferation as indicated by positive staining of the phosphorylated CHK2 (pCHK2) and PCNA, respectively. Left: The normal/CIN1 and CIN2 samples were derived from the same patient and the black arrowheads indicate a transition site between normal and CIN1 tissues in the patient sample. Right: The CIN3 and cancer samples were derived from the same patient. The images in (B) and (C) are adapted from Oncogene [27] with permission from Springer/Nature.

Fig. (3)

The activation of the TERT gene transcription and telomerase mediated by oncogenic events during oncogenesis. Oncogenic factors disrupt the balance between TERT repressors and activators, and/or induce genetic aberrations, and epigenetic alterations at the TERT locus, thereby leading to the trans-activation of the TERT gene. These oncogenic factors may also promote aberrant mRNA splicing, dysregulation of non-coding RNAs (ncRNAs) and/or phosphorylation ubiqitination, through which TERT expression is further amplified at post-transcriptional and post-translational levels. Eventually, TERT expression and telomerase activity is induced in transformed cells. TS: Tumor suppressor.

Fig. (4)

Multiple telomere-related factors are targeted by oncogenic events to maintain telomere stabilization/protection, unlimited proliferation and other hallmarks of cancer cells. Telomere length and structure is interdependent with each other. The oncogenic event targets one or more components in telomere length maintenance and/or telomere chromatin for telomere stabilization and protection during the malignant transformation and cancer progression.