Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

Abstract

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.

Fig. 1

Multiple oncogeneic roles for TERT in cancer development and progression. TERT/telomerase activation is required for transformation of human cells and infinite proliferation by stabilizing telomere length (Telomere lengthening-dependent). The telomere lengthening-independent functions of TERT significantly contribute to cancer initiation/progression, which include its effects on mitochondria, ubiquitin-proteasomal system (UPS), gene transcription, microRNA (miRNA) expression, DNA damage repair, RNA-dependent RNA polymerase (RdRP) activity. CF co-factor; EMT epithelial-mesenchymal transition, TF transcription factor. The effect of TERT on UPS predominantly occurs in the nucleus, but is also possible in the cytoplasma

Fig. 2

TERT promoter mutations in human cancer. a Schematic presentation of TERT promoter mutations and relevant transcription factors. The TERT gene at chromosome 5p and its promoter is shown. C > T mutation occurs at one of both positions of the TERT proximal promoter (−124 and −146 to ATG for C228T and C250T, respectively) in malignant cells, which create de novo ETS binding motifs. The ETS family members GABPA and GABPB form heterotetramers that bind to the de novo ETS site and activate TERT transcription. The E-box (CACGTG) sequence mutation was recently identified in clear cell renal cell carcinoma (ccRCC), which may lead to the dissociation of the repressor MAX/Mad1 complex from E-box, thereby de-repressing the TERT gene. b The frequency of TERT promoter mutations in a panel cancer types from the TCGA dataset analyses [49]. GBM glioblastoma multiforme, SKCM skin cutaneous melanoma, BLCA bladder urothelial carcinoma, LIHC liver hepatocellular carcinoma, LGG brain lower-grade glioma, HNSC head and neck squamous cell carcinoma, THCA thyroid carcinoma, KICH kidney chromophobe, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, ACC adrenocortical carcinoma, PRAD prostate adenocarcinoma, LUAD lung adenocarcinoma, BRCA breast invasive carcinoma, STAD stomach adenocarcinoma, ESCA esophageal carcinoma, OV ovarian serous cystadenocarcinoma, DLBC lymphoid neoplasm diffuse large B cell lymphoma, KIRP kidney renal papillary cell carcinoma, KIRC kidney renal clear cell carcinoma, UVM Uveal melanoma, SARC sarcoma, CRC colorectal carcinoma, LAML acute myeloid leukemia, LUSC lung squamous cell carcinoma, UCEC uterine corpus endometrial carcinoma

Fig. 3

The structural alterations and amplification of the TERT gene in human cancer. a Schematic presentation of rearrangements and onco-viral insertation of the TERT locus. Left: The rearrangements occur most frequently in a 50 kb region proximal of the TERT gene, although the translocation to other chromsomes is also observed. The rearrangements are not random events, which often juxtapose the TERT coding sequence to strong enhancer elements. Right: Most integration breakpoints for onco-viral insertions are located in the TERT promoter region, and almost all the integrations contained at least one viral gene enhancer or promoter. b and c The structural variants and amplification of the TERT gene in a panel of human malignancies from the TCGA cohort analyses, respectively. GBM glioblastoma multiforme, SKCM skin cutaneous melanoma, BLCA bladder urothelial carcinoma, LIHC liver hepatocellular carcinoma, LGG brain lower-grade glioma, HNSC head and neck squamous cell carcinoma, THCA thyroid carcinoma, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, ACC adrenocortical carcinoma, PRAD prostate adenocarcinoma, LUSC lung squamous cell carcinoma, LUAD lung adenocarcinoma, PCPG Pheochromocytoma and paraganglioma, LUSC lung squamous cell carcinoma, TGCT testicular germ cell tumor, BRCA breast invasive carcinoma, STAD stomach adenocarcinoma, ESCA esophageal carcinoma, OV ovarian serous cystadenocarcinoma, DLBC lymphoid neoplasm diffuse large B cell lymphoma, KIRP kidney renal papillary cell carcinoma, KIRC kidney renal clear cell carcinoma, KICH kidney chromophobe, UVM uveal melanoma, SARC sarcoma, THYM thymus, CRC colorectal carcinoma, LAML acute myeloid leukemia, UCEC uterine corpus endometrial carcinoma, CHOL cholangiocarcinoma