%0 Journal Article
%A von Knebel Doeberitz, Nikolaus
%A Paech, Daniel
%A Sturm, Dominik
%A Pusch, Stefan
%A Turcan, Sevin
%A Saunthararajah, Yogen
%T Changing paradigms in oncology: toward non-cytotoxic treatments for advanced gliomas.
%J International journal of cancer
%V 151
%N 9
%@ 0020-7136
%C Bognor Regis
%I Wiley-Liss
%M DKFZ-2022-01045
%P 1431-1446
%D 2022
%Z #EA:E010# / 2022 Nov 1;151(9):1431-1446
%X 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 non-cytotoxic glioma-therapy.
%K Cancer Epigenetics (Other)
%K Epigenetic Glioma Therapy (Other)
%K Glioma (Other)
%K Glioma Therapy (Other)
%K Neurooncology (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35603902
%R 10.1002/ijc.34131
%U https://inrepo02.dkfz.de/record/180028