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Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70–80% of H3K27M DIPG, and...

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Autores principales: Nikolaev, Anatoly, Fiveash, John B., Yang, Eddy S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014308/
https://www.ncbi.nlm.nih.gov/pubmed/31940975
http://dx.doi.org/10.3390/ijms21020490
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author Nikolaev, Anatoly
Fiveash, John B.
Yang, Eddy S.
author_facet Nikolaev, Anatoly
Fiveash, John B.
Yang, Eddy S.
author_sort Nikolaev, Anatoly
collection PubMed
description Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70–80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 μM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation.
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spelling pubmed-70143082020-03-09 Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG Nikolaev, Anatoly Fiveash, John B. Yang, Eddy S. Int J Mol Sci Article Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70–80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 μM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation. MDPI 2020-01-13 /pmc/articles/PMC7014308/ /pubmed/31940975 http://dx.doi.org/10.3390/ijms21020490 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nikolaev, Anatoly
Fiveash, John B.
Yang, Eddy S.
Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG
title Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG
title_full Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG
title_fullStr Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG
title_full_unstemmed Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG
title_short Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG
title_sort combined targeting of mutant p53 and jumonji family histone demethylase augments therapeutic efficacy of radiation in h3k27m dipg
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014308/
https://www.ncbi.nlm.nih.gov/pubmed/31940975
http://dx.doi.org/10.3390/ijms21020490
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