Dataset Information

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

ABSTRACT:

Background

Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.

Results

We investigate the alterations of 5hmC and TET enzymes in MB and their significance to cerebellar cancer formation. We show total abundance of 5hmC is reduced in MB, but identify significant enrichment of MB-specific 5hmC marks at regulatory regions of genes implicated in stem-like properties and Nanog-binding motifs. While TET1 and TET2 levels are high in MBs, only knockout of Tet1 in the smoothened (SmoA1) mouse model attenuates uncontrolled proliferation, leading to a favorable prognosis. The pharmacological Tet1 inhibition reduces cell viability and platelet-derived growth factor signaling pathway-associated genes.

Conclusions

These results together suggest a potential key role of 5hmC and indicate an oncogenic nature for TET1 in MB tumorigenesis, suggesting it as a potential therapeutic target for MBs.

SUBMITTER: Kim H

PROVIDER: S-EPMC8082834 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Kim Hyerim H Kang Yunhee Y Li Yujing Y Chen Li L Lin Li L Johnson Nicholas D ND Zhu Dan D Robinson M Hope MH McSwain Leon L Barwick Benjamin G BG Yuan Xianrui X Liao Xinbin X Zhao Jie J Zhang Zhiping Z Shu Qiang Q Chen Jianjun J Allen Emily G EG Kenney Anna M AM Castellino Robert C RC Van Meir Erwin G EG Conneely Karen N KN Vertino Paula M PM Jin Peng P Li Jian J

Genome biology 20210429 1

<h4>Background</h4>Medulloblastoma (MB) is the most common malignant pediatric brain tumor that originates in the cerebellum and brainstem. Frequent somatic mutations and deregulated expression of epigenetic regulators in MB highlight the substantial role of epigenetic alterations. 5-hydroxymethylcytosine (5hmC) is a highly abundant cytosine modification in the developing cerebellum and is regulated by ten-eleven translocation (TET) enzymes.<h4>Results</h4>We investigate the alterations of 5hmC ...[more]

PMID: 33926529

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Project description:Background and aimsCholangiocarcinoma (CCA) is a highly lethal disease without effective therapeutic approaches. The whole-genome sequencing data indicate that about 20% of patients with CCA have isocitrate dehydrogenase 1 (IDH1) mutations, which have been suggested to target 2-oxoglutarate (OG)-dependent dioxygenases in promoting CCA carcinogenesis. However, the clinical study indicates that patients with CCA and mutant IDH1 have better prognosis than those with wild-type IDH1, further complicating the roles of 2-OG-dependent enzymes.Approach and resultsThis study aimed to clarify if ten-eleven translocation 1 (TET1), which is one of the 2-OG-dependent enzymes functioning in regulating 5-hydroxymethylcytosine (5hmC) formation, is involved in CCA progression. By analyzing The Cancer Genome Atlas (TCGA) data set, TET1 mRNA was found to be substantially up-regulated in patients with CCA when compared with noncancerous bile ducts. Additionally, TET1 protein expression was significantly elevated in human CCA tumors. CCA cells were challenged with α-ketoglutarate (α-KG) and dimethyl-α-KG (DM-α-KG), which are cosubstrates for TET1 dioxygenase. The treatments with α-KG and DM-α-KG promoted 5hmC formation and malignancy of CCA cells. Molecular and pharmacological approaches were used to inhibit TET1 activity, and these treatments substantially suppressed 5hmC and CCA carcinogenesis. Mechanistically, it was found that knockdown of TET1 may suppress CCA progression by targeting cell growth and apoptosis through epigenetic regulation. Consistently, targeting TET1 significantly inhibited CCA malignant progression in a liver orthotopic xenograft model by targeting cell growth and apoptosis.ConclusionsOur data suggest that expression of TET1 is highly associated with CCA carcinogenesis. It will be important to evaluate TET1 expression in CCA tumors before application of the IDH1 mutation inhibitor because the inhibitor suppresses 2-hydroxyglutarate expression, which may result in activation of TET, potentially leading to CCA malignancy.

Project description:Mesenchymal stem cells (MSCs) have emerged as crucial players within the tumor microenvironment (TME), contributing through their paracrine secretome. Depending on the context, the MSC-derived secretome can either support or inhibit tumor growth. This study investigates the role of MSC-derived secretome in modulating breast cancer (BC) cell behavior, with a focus on ten-eleven translocation 1 (TET1), a DNA demethylase with known oncogenic properties in triple-negative breast cancer (TNBC). We first isolated and characterized human bone marrow-derived MSCs, and then assessed the impact of their secretome on BC cells. Treatment with the MSC-derived secretome significantly inhibited the proliferation and migration of both MDA-MB-231 and MCF-7 BC cell lines, resulting in reduced cell viability and migration rates compared to control cells. Western blot analyses revealed downregulation of Cyclin D1 and c-Myc, along with decreased expression of N-cadherin and increased expression of E-cadherin, indicating potential inhibition of the epithelial-to-mesenchymal transition. Differential gene expression analyses highlighted TET1 as significantly upregulated in TNBC tissues compared to normal samples. Further experiments confirmed that the MSC-derived secretome downregulated TET1 expression in BC cells, as evidenced by RT-qPCR and western blot analyses. To explore TET1's functional role, we silenced TET1 with siRNAs, observing cell cycle arrest and enhanced apoptosis-effects that mirrored those seen with MSC-secretome treatment. Notably, TET1 knockdown also increased MDA-MB-231 cell sensitivity to cisplatin, suggesting a role for TET1 in chemoresistance. These findings provide insight into the ability of MSCs to modulate BC cell progression through their secretome, highlighting the involvement of TET1 downregulation in inhibiting BC cell progression and enhancing cisplatin chemosensitivity. The MSC-derived secretome thus holds promise as an innovative, cell-free therapeutic approach in BC treatment.

Dataset Information

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Background

Results

Conclusions

Publications

Ten-eleven translocation protein 1 modulates medulloblastoma progression.

Similar Datasets

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