Human telomerase reverse transcriptase is a novel target of Hippo‐YAP pathway

Zhang, Qian; Liu, Ning; Bai, Junjie; Zhou, Qi; Mao, Jian; Xu, Lu; Liu, Jiang; Wei, Haibin; Ren, Chengcheng; Wu, Xiaoying; Wang, Miao; Zhao, Bin; Cong, Yu‐Sheng

doi:10.1096/fj.201902147r

Cited by 15 publications

(8 citation statements)

References 44 publications

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“…Although both dormant CSCs and active EPCs share the signaling pathways of YAP, WNT and TGF‐ β , TGF‐ β signaling is more active in CSCs than in EPCs. Interestingly, YAP and WNT can activate telomerase, [ 53 ] while TGF‐ β inhibits TERT expression and telomerase activity. [ 54 ] Higher TGF‐ β signaling in CSCs is consistent with their minimal telomerase activity and quiescent state.…”

Section: Discussionmentioning

confidence: 99%

Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single‐Cell Analysis of Transcriptome and Telomeres

et al. 2021

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Cancer stem cells (CSCs) presumably contribute to tumor progression and drug resistance, yet their definitive features have remained elusive. Here, simultaneous measurement of telomere length and transcriptome in the same cells enables systematic assessment of CSCs in primary colorectal cancer (CRC). The in-depth transcriptome profiled by SMART-seq2 is independently validated by high-throughput scRNA-seq using 10 × Genomics. It is found that rare CSCs exist in dormant state and display plasticity toward cancer epithelial cells (EPCs) that essentially are presumptive tumor-initiating cells (TICs), while both retaining the prominent signaling pathways including WNT, TGF-, and HIPPO/YAP. Moreover, CSCs exhibit chromosome copy number variation (CNV) pattern resembling cancer EPCs but distinct from normal stem cells, suggesting the phylogenetic relationship between CSCs and cancer EPCs. Notably, CSCs maintain shorter telomeres and possess minimal telomerase activity consistent with their nonproliferative nature, unlike cancer EPCs. Additionally, the specific signature of CSCs particularly NOTUM, SMOC2, BAMBI, PHLDA1, and TNFRSF19 correlates with the prognosis of CRC. These findings characterize the heterogeneity of CSCs and their linkage to cancer EPCs/TICs, some of which are conventionally regarded as CSCs.

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Section: Discussionmentioning

confidence: 99%

Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single‐Cell Analysis of Transcriptome and Telomeres

et al. 2021

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“…For complicated reasons, transgenic products are not widely accepted by consumers, and more reliable and acceptable methods of gene editing can be used in cultured meat research. For example, through CRISPR/Cas9-mediated gene knockout, negative regulators upstream of YAP (Mst1/2 or Lats1/2) can be depleted to achieve sustained activation of YAP signaling [39]. Additionally, YAP and other positive regulators of MuSCs, such as Pax7, can be activated endogenously via CRISPR/dCas9 (d: dead) system without introducing exogenous genes [40].…”

Section: Discussionmentioning

confidence: 99%

YAP Promotes Cell Proliferation and Stemness Maintenance of Porcine Muscle Stem Cells under High-Density Condition

Liu

Zhu

et al. 2021

Cells

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Muscle stem cells (MuSCs) isolated ex vivo are essential original cells to produce cultured meat. Currently, one of the main obstacles for cultured meat production derives from the limited capacity of large-scale amplification of MuSCs, especially under high-density culture condition. Here, we show that at higher cell densities, proliferation and differentiation capacities of porcine MuSCs are impaired. We investigate the roles of Hippo-YAP signaling, which is important regulators in response to cell contact inhibition. Interestingly, abundant but not functional YAP proteins are accumulated in MuSCs seeded at high density. When treated with lysophosphatidic acid (LPA), the activator of YAP, porcine MuSCs exhibit increased proliferation and elevated differentiation potential compared with control cells. Moreover, constitutively active YAP with deactivated phosphorylation sites, but not intact YAP, promotes cell proliferation and stemness maintenance of MuSCs. Together, we reveal a potential molecular target that enables massive MuSCs expansion for large-scale cultured meat production under high-density condition.

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“…Quantitative real‐time PCR was used to measure relative telomere length based on previously described (Zhang et al , 2020). Genome DNA was extracted from cells using DNeasy Blood & Tissue Kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment

et al. 2022

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Telomerase plays a pivotal role in tumorigenesis by both telomeredependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observe that expression of telomerase reverse transcriptase (TERT) is closely associated with immunosuppressive signatures. We demonstrate that TERT can activate a subclass of endogenous retroviruses (ERVs) independent of its telomerase activity to form double-stranded RNAs (dsRNAs), which are sensed by the RIG-1/MDA5-MAVS signalling pathway and trigger interferon signalling in cancer cells. Furthermore, we show that TERT-induced ERV/interferon signalling stimulates the expression of chemokines, including CXCL10, which induces the infiltration of suppressive Tcell populations with increased percentage of CD4 + and FOXP3 + cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERV/interferon signalling contributes to immune suppression in tumours.

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Human telomerase reverse transcriptase is a novel target of Hippo‐YAP pathway

Cited by 15 publications

References 44 publications

Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single‐Cell Analysis of Transcriptome and Telomeres

Colorectal Cancer Stem Cell States Uncovered by Simultaneous Single‐Cell Analysis of Transcriptome and Telomeres

YAP Promotes Cell Proliferation and Stemness Maintenance of Porcine Muscle Stem Cells under High-Density Condition

TERT activates endogenous retroviruses to promote an immunosuppressive tumour microenvironment

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