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MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION

Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link bet...

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Autores principales: Yang, Zeng-jie, Yang, Yijun, Heller, Allie, Rives, Silvia Valdes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260136/
http://dx.doi.org/10.1093/neuonc/noad073.241
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author Yang, Zeng-jie
Yang, Yijun
Heller, Allie
Rives, Silvia Valdes
author_facet Yang, Zeng-jie
Yang, Yijun
Heller, Allie
Rives, Silvia Valdes
author_sort Yang, Zeng-jie
collection PubMed
description Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link between TH signaling and MB pathogenicity is unknown. Here, we found that TH plays a critical role in MB pathogenicity through regulating the terminal differentiation of tumor cells. In the absence or with reduced levels of TH, unliganded TRα (a nuclear TH receptor) physically interacts with EZH2 to epigenetically repress the expression of NeuroD1, a transcription factor dictating terminal differentiation of neuronal progenitors and MB cells. However, TH reverses EZH2-mediated repression of NeuroD1 through interfering with the binding between EZH2 and TRα, thereby stimulating terminal differentiation of tumor cells and repressing MB pathogenicity. Moreover, TH promotes extensive differentiation and suppresses the proliferation of tumor cells from different molecular subgroups of MB5 including hedgehog (HH) group as well as group 3 (G3) MB, suggesting that TH-induced differentiation is not restricted by oncogenic mutations in tumor cells. Consequently, TH treatment significantly inhibits the in vivo growth of SHH- and G3-MB via stimulating tumor cell differentiation, with no induction of tumor cell apoptosis or death, indicating that TH signaling represents a novel therapeutic entry-point for broad treatment of MB. These findings elucidate the mechanisms underlying terminal differentiation of MB cells, establish an unprecedented association between TH signaling and MB progression. Our studies provide compelling evidence for a promising tumor therapeutic modality by promoting tumor cell differentiation.
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spelling pubmed-102601362023-06-13 MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION Yang, Zeng-jie Yang, Yijun Heller, Allie Rives, Silvia Valdes Neuro Oncol Final Category: Medulloblastomas - MDB Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link between TH signaling and MB pathogenicity is unknown. Here, we found that TH plays a critical role in MB pathogenicity through regulating the terminal differentiation of tumor cells. In the absence or with reduced levels of TH, unliganded TRα (a nuclear TH receptor) physically interacts with EZH2 to epigenetically repress the expression of NeuroD1, a transcription factor dictating terminal differentiation of neuronal progenitors and MB cells. However, TH reverses EZH2-mediated repression of NeuroD1 through interfering with the binding between EZH2 and TRα, thereby stimulating terminal differentiation of tumor cells and repressing MB pathogenicity. Moreover, TH promotes extensive differentiation and suppresses the proliferation of tumor cells from different molecular subgroups of MB5 including hedgehog (HH) group as well as group 3 (G3) MB, suggesting that TH-induced differentiation is not restricted by oncogenic mutations in tumor cells. Consequently, TH treatment significantly inhibits the in vivo growth of SHH- and G3-MB via stimulating tumor cell differentiation, with no induction of tumor cell apoptosis or death, indicating that TH signaling represents a novel therapeutic entry-point for broad treatment of MB. These findings elucidate the mechanisms underlying terminal differentiation of MB cells, establish an unprecedented association between TH signaling and MB progression. Our studies provide compelling evidence for a promising tumor therapeutic modality by promoting tumor cell differentiation. Oxford University Press 2023-06-12 /pmc/articles/PMC10260136/ http://dx.doi.org/10.1093/neuonc/noad073.241 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Final Category: Medulloblastomas - MDB
Yang, Zeng-jie
Yang, Yijun
Heller, Allie
Rives, Silvia Valdes
MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION
title MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION
title_full MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION
title_fullStr MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION
title_full_unstemmed MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION
title_short MDB-08. THYROID HORMONES INHIBIT MEDULLOBLASTOMA PROGRESSION THROUGH INDUCING TUMOR CELL DIFFERENTIATION
title_sort mdb-08. thyroid hormones inhibit medulloblastoma progression through inducing tumor cell differentiation
topic Final Category: Medulloblastomas - MDB
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260136/
http://dx.doi.org/10.1093/neuonc/noad073.241
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