TY  - JOUR
AU  - von Knebel Doeberitz, Nikolaus
AU  - Paech, Daniel
AU  - Sturm, Dominik
AU  - Pusch, Stefan
AU  - Turcan, Sevin
AU  - Saunthararajah, Yogen
TI  - Changing paradigms in oncology: toward non-cytotoxic treatments for advanced gliomas.
JO  - International journal of cancer
VL  - 151
IS  - 9
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2022-01045
SP  - 1431-1446
PY  - 2022
N1  - #EA:E010# / 2022 Nov 1;151(9):1431-1446
AB  - 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.
KW  - Cancer Epigenetics (Other)
KW  - Epigenetic Glioma Therapy (Other)
KW  - Glioma (Other)
KW  - Glioma Therapy (Other)
KW  - Neurooncology (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35603902
DO  - DOI:10.1002/ijc.34131
UR  - https://inrepo02.dkfz.de/record/180028
ER  -