Changing paradigms in oncology: Toward noncytotoxic treatments for advanced gliomas.


Journal

International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124

Informations de publication

Date de publication:
01 11 2022
Historique:
revised: 12 05 2022
received: 23 02 2022
accepted: 13 05 2022
pubmed: 24 5 2022
medline: 15 9 2022
entrez: 23 5 2022
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 35603902
doi: 10.1002/ijc.34131
pmc: PMC9474618
mid: NIHMS1810009
doi:

Substances chimiques

Chromatin 0
Cyclin-Dependent Kinase Inhibitor p16 0
Transcription Factors 0
Tumor Suppressor Protein p53 0

Types de publication

Journal Article Review Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1431-1446

Subventions

Organisme : NCI NIH HHS
ID : R01 CA138858
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204373
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA263430
Pays : United States
Organisme : NHLBI NIH HHS
ID : R44 HL135896
Pays : United States

Informations de copyright

© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

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Auteurs

Nikolaus von Knebel Doeberitz (N)

Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Daniel Paech (D)

Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Neuroradiology, Bonn University Hospital, Bonn, Germany.

Dominik Sturm (D)

Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany.
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg, Germany.

Stefan Pusch (S)

Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
German Cancer Consortium (DKTK), Clinical Cooperation Unit (CCU) Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Sevin Turcan (S)

Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.

Yogen Saunthararajah (Y)

Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.

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