Telomerase: Key regulator of inflammation and cancer

Wu, Lixian; Fidan, Kerem; Um, Jae‐Young; Ahn, Kwang Seok

doi:10.1016/j.phrs.2020.104726

Cited by 45 publications

(34 citation statements)

References 201 publications

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“…These data support our statement that TERT promoter mutations are acquired during tumor progression after the initial FOXL2 C402G driver mutation. Although targeting telomerase as an anticancer treatment may represent an attractive strategy for recurrent aGCT, the development of efficacious cancer-specific telomerase inhibitors remains an ongoing challenge [26]. Using a combination of WGS and targeted sequencing, the results of the current study demonstrate that KMT2D undergoes frequent inactivating mutations in aGCTs.…”

Section: Discussionmentioning

confidence: 77%

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Pilsworth

Cochrane²,

Neilson³

et al. 2021

The Journal of Pathology CR

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Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.

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Section: Discussionmentioning

confidence: 77%

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Pilsworth

Cochrane²,

Neilson³

et al. 2021

The Journal of Pathology CR

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“…TERT can also interact with mitochondrial RNA processing endoribonuclease (RMRP) and use the RNA-dependent RNA polymerase to synthesize dsRNA. Mutations in RMRP can interfere with RMRP-TERT binding, contributing to pleiotropic syndrome cartilage–hair hypoplasia ( 190 ).…”

Section: Involvement Of Tert In Non-telomere-related Mechanismsmentioning

confidence: 99%

TERT—Regulation and Roles in Cancer Formation

et al. 2020

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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.

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“…Additionally, enhanced tumorigenesis by TERT overexpression occurred by activating various pathways including cell proliferation, anti-apoptosis and energy metabolism [ 55 – 57 ]. Mitochondrial TERT has been shown to reduce intracellular ROS production and hence, reduced ROS-induced cell death [ 57 – 59 ]. Furthermore, TERT inhibits cytosolic acidification, translocation of Bax, and the release of cytochrome C to the cytosol, which eventually inhibits apoptosis [ 60 ].…”

Section: The Telomerase Complexmentioning

confidence: 99%

Non-canonical roles of canonical telomere binding proteins in cancers

Akıncılar

Chan

et al. 2021

Cell. Mol. Life Sci.

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Reactivation of telomerase is a major hallmark observed in 90% of all cancers. Yet paradoxically, enhanced telomerase activity does not correlate with telomere length and cancers often possess short telomeres; suggestive of supplementary non-canonical roles that telomerase might play in the development of cancer. Moreover, studies have shown that aberrant expression of shelterin proteins coupled with their release from shortening telomeres can further promote cancer by mechanisms independent of their telomeric role. While targeting telomerase activity appears to be an attractive therapeutic option, this approach has failed in clinical trials due to undesirable cytotoxic effects on stem cells. To circumvent this concern, an alternative strategy could be to target the molecules involved in the non-canonical functions of telomeric proteins. In this review, we will focus on emerging evidence that has demonstrated the non-canonical roles of telomeric proteins and their impact on tumorigenesis. Furthermore, we aim to address current knowledge gaps in telomeric protein functions and propose future research approaches that can be undertaken to achieve this.

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Telomerase: Key regulator of inflammation and cancer

Cited by 45 publications

References 201 publications

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

TERT—Regulation and Roles in Cancer Formation

Non-canonical roles of canonical telomere binding proteins in cancers

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