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Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas
Glial‐lineage malignancies (gliomas) recurrently mutate and/or delete the master regulators of apoptosis p53 and/or p16/CDKN2A, undermining apoptosis‐intending (cytotoxic) treatments. By contrast to disrupted p53/p16, glioma cells are live‐wired with the master transcription factor circuits that spe...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9474618/ https://www.ncbi.nlm.nih.gov/pubmed/35603902 http://dx.doi.org/10.1002/ijc.34131 |
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author | von Knebel Doeberitz, Nikolaus Paech, Daniel Sturm, Dominik Pusch, Stefan Turcan, Sevin Saunthararajah, Yogen |
author_facet | von Knebel Doeberitz, Nikolaus Paech, Daniel Sturm, Dominik Pusch, Stefan Turcan, Sevin Saunthararajah, Yogen |
author_sort | von Knebel Doeberitz, Nikolaus |
collection | PubMed |
description | Glial‐lineage malignancies (gliomas) recurrently mutate and/or delete the master regulators of apoptosis p53 and/or p16/CDKN2A, undermining apoptosis‐intending (cytotoxic) treatments. By contrast to disrupted p53/p16, glioma cells are live‐wired with the master transcription factor circuits that specify and drive glial lineage fates: these transcription factors activate early‐glial and replication programs as expected, but fail in their other usual function of forcing onward glial lineage‐maturation—late‐glial genes have constitutively “closed” chromatin requiring chromatin‐remodeling for activation—glioma‐genesis disrupts several epigenetic components needed to perform this work, and simultaneously amplifies repressing epigenetic machinery instead. Pharmacologic inhibition of repressing epigenetic enzymes thus allows activation of late‐glial genes and terminates glioma self‐replication (self‐replication = replication without lineage‐maturation), independent of p53/p16/apoptosis. Lineage‐specifying master transcription factors therefore contrast with p53/p16 in being enriched in self‐replicating glioma cells, reveal a cause‐effect relationship between aberrant epigenetic repression of late‐lineage programs and malignant self‐replication, and point to specific epigenetic targets for noncytotoxic glioma‐therapy. |
format | Online Article Text |
id | pubmed-9474618 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94746182022-10-14 Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas von Knebel Doeberitz, Nikolaus Paech, Daniel Sturm, Dominik Pusch, Stefan Turcan, Sevin Saunthararajah, Yogen Int J Cancer Invited Review Glial‐lineage malignancies (gliomas) recurrently mutate and/or delete the master regulators of apoptosis p53 and/or p16/CDKN2A, undermining apoptosis‐intending (cytotoxic) treatments. By contrast to disrupted p53/p16, glioma cells are live‐wired with the master transcription factor circuits that specify and drive glial lineage fates: these transcription factors activate early‐glial and replication programs as expected, but fail in their other usual function of forcing onward glial lineage‐maturation—late‐glial genes have constitutively “closed” chromatin requiring chromatin‐remodeling for activation—glioma‐genesis disrupts several epigenetic components needed to perform this work, and simultaneously amplifies repressing epigenetic machinery instead. Pharmacologic inhibition of repressing epigenetic enzymes thus allows activation of late‐glial genes and terminates glioma self‐replication (self‐replication = replication without lineage‐maturation), independent of p53/p16/apoptosis. Lineage‐specifying master transcription factors therefore contrast with p53/p16 in being enriched in self‐replicating glioma cells, reveal a cause‐effect relationship between aberrant epigenetic repression of late‐lineage programs and malignant self‐replication, and point to specific epigenetic targets for noncytotoxic glioma‐therapy. John Wiley & Sons, Inc. 2022-06-16 2022-11-01 /pmc/articles/PMC9474618/ /pubmed/35603902 http://dx.doi.org/10.1002/ijc.34131 Text en © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Invited Review von Knebel Doeberitz, Nikolaus Paech, Daniel Sturm, Dominik Pusch, Stefan Turcan, Sevin Saunthararajah, Yogen Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas |
title | Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas |
title_full | Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas |
title_fullStr | Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas |
title_full_unstemmed | Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas |
title_short | Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas |
title_sort | changing paradigms in oncology: toward noncytotoxic treatments for advanced gliomas |
topic | Invited Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9474618/ https://www.ncbi.nlm.nih.gov/pubmed/35603902 http://dx.doi.org/10.1002/ijc.34131 |
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