Three‐dimensional nuclear telomere architecture changes during endometrial carcinoma development

Danescu, Adrian; Gonzalez, Sandra Herrero; Cristofano, Antonio Di; Mai, Sabine; Hombach‐Klonisch, Sabine

doi:10.1002/gcc.22067

Cited by 9 publications

(6 citation statements)

References 80 publications

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“…Having shown that HMGA2 diminishes telomere-mediated genomic instability in human cancer cells, we wanted to determine if the loss of this telomere protective role of HMGA2 involves changes in 3D telomere architecture [ 47 – 49 ]. For these studies, we used C1 cells +/− dox to regulate the level of endogenously produced HMGA2.…”

Section: Resultsmentioning

confidence: 99%

High Mobility Group A2 protects cancer cells against telomere dysfunction

et al. 2016

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The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. Here we show that HMGA2 localizes to mammalian telomeres and enhances telomere stability in cancer cells. We present a novel interaction of HMGA2 with the key shelterin protein TRF2. We found that the linker (L1) region of HMGA2 contributes to this interaction but the ATI-L1-ATII molecular region of HMGA2 is required for strong interaction with TRF2. This interaction was independent of HMGA2 DNA-binding and did not require the TRF2 interacting partner RAP1 but involved the homodimerization and hinge regions of TRF2. HMGA2 retained TRF2 at telomeres and reduced telomere-dysfunction despite induced telomere stress. Silencing of HMGA2 resulted in (i) reduced binding of TRF2 to telomere DNA as observed by ChIP, (ii) increased telomere instability and (iii) the formation of telomere dysfunction-induced foci (TIF). This resulted in increased telomere aggregation, anaphase bridges and micronuclei. HMGA2 prevented ATM-dependent pTRF2T188 phosphorylation and attenuated signaling via the telomere specific ATM-CHK2-CDC25C DNA damage signaling axis. In summary, our data demonstrate a unique and novel role of HMGA2 in telomere protection and promoting telomere stability in cancer cells. This identifies HMGA2 as a new therapeutic target for the destabilization of telomeres in HMGA2+ cancer cells.

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Section: Resultsmentioning

confidence: 99%

High Mobility Group A2 protects cancer cells against telomere dysfunction

et al. 2016

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“…A significantly increased number of telomere aggregates was observed in atypical hyperplastic cells in a mouse models which is also a specific feature of cancer cells. Moreover, the PTEN heterozygous mouse model further demonstrated that 3D telomere architectural changes occur before the complete loss of PTEN and prior to the development of histological characteristics of atypical hyperplasia and endometrial carcinoma (251). Therefore, the presence of telomere aggregates in hyperproliferative lesions with atypical nuclei may render them to be precancerous changes.…”

Section: Endometriummentioning

confidence: 99%

Telomerase and Telomeres in Endometrial Cancer

et al. 2019

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Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the “end replication problem” as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80–90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.

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“…In turn, the carcinoma in situ of the endometrium; also called intraepithelial neoplasia, progresses in some cases in less than a year to endometrial adenocarcinoma 114 . Among the molecular events associated with the progression of carcinomas in situ is the gain in the expression and activity of telomerase, as well as the extension of telomeres [115][116][117] . The 80% of sporadic endometrial adenocarcinomas show endometrioid histology 114 .…”

Section: Box 2 Conserved Process In Epithelial Carcinogenesismentioning

confidence: 99%

From Molecular Biology to Epithelial Carcinogenesis

Méndez¹

2021

Preprint

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The theory of the origin of carcinomas suggests that neoplasias from epithelial tissues are the consequence of the reactivation of developmental programs. It proposes a model in which the epithelial cells undergo cellular transitions due to replicative senescence and inflammation towards a mesenchymal-undifferentiated phenotype with cancerous behavior. The conserved pattern of histological progression and the molecular biology of carcinomas is congruent with the view of cancer as a developmental disease. In support of the theory, the experimental literature regarding the molecular, cellular, and histopathological mechanisms associated with epithelial carcinogenesis were aligned according to the premises of the hypothesis. Thereby identified a generic process in the carcinogenesis of the breast, endometrium, prostate, colon, lung, pancreas, bladder, liver, and cervix. Then, is provided a methodology overview of modeling in systems biology derived from previous research testing the hypothesis. The results illustrate the value of the complex systems approach to recover behavior that cannot be inferred only by traditional methods. Specifically, the model suggests that the consistency in the cell types and the directionality of the observed cellular transitions during epithelial carcinogenesis arise from structural constraints in the molecular networks associated with the carcinomas. Overall, the results of the dynamical analysis agree with the premises of the hypothesis and provide an insightful perspective of the potential mechanisms underlying the cellular plasticity displayed during epithelial carcinogenesis. In an era of big data and yet few advances in the underlying causes of chronic diseases, the manuscript also aims to inspire molecular biologists to integrate existing empirical evidence with systems biology modeling in the pursuit of understanding.

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Three‐dimensional nuclear telomere architecture changes during endometrial carcinoma development

Cited by 9 publications

References 80 publications

High Mobility Group A2 protects cancer cells against telomere dysfunction

High Mobility Group A2 protects cancer cells against telomere dysfunction

Telomerase and Telomeres in Endometrial Cancer

From Molecular Biology to Epithelial Carcinogenesis

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