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VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells

We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-H3K27M cell fitness. Gene expression studies after VRK3 knockdown...

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Autores principales: Menez, Virginie, Kergrohen, Thomas, Shasha, Tal, Silva-Evangelista, Claudia, Le Dret, Ludivine, Auffret, Lucie, Subecz, Chloé, Lancien, Manon, Ajlil, Yassine, Vilchis, Irma Segoviano, Beccaria, Kévin, Blauwblomme, Thomas, Oberlin, Estelle, Grill, Jacques, Castel, David, Debily, Marie-Anne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599138/
https://www.ncbi.nlm.nih.gov/pubmed/37886173
http://dx.doi.org/10.3389/fonc.2023.1229312
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author Menez, Virginie
Kergrohen, Thomas
Shasha, Tal
Silva-Evangelista, Claudia
Le Dret, Ludivine
Auffret, Lucie
Subecz, Chloé
Lancien, Manon
Ajlil, Yassine
Vilchis, Irma Segoviano
Beccaria, Kévin
Blauwblomme, Thomas
Oberlin, Estelle
Grill, Jacques
Castel, David
Debily, Marie-Anne
author_facet Menez, Virginie
Kergrohen, Thomas
Shasha, Tal
Silva-Evangelista, Claudia
Le Dret, Ludivine
Auffret, Lucie
Subecz, Chloé
Lancien, Manon
Ajlil, Yassine
Vilchis, Irma Segoviano
Beccaria, Kévin
Blauwblomme, Thomas
Oberlin, Estelle
Grill, Jacques
Castel, David
Debily, Marie-Anne
author_sort Menez, Virginie
collection PubMed
description We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-H3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201.
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spelling pubmed-105991382023-10-26 VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells Menez, Virginie Kergrohen, Thomas Shasha, Tal Silva-Evangelista, Claudia Le Dret, Ludivine Auffret, Lucie Subecz, Chloé Lancien, Manon Ajlil, Yassine Vilchis, Irma Segoviano Beccaria, Kévin Blauwblomme, Thomas Oberlin, Estelle Grill, Jacques Castel, David Debily, Marie-Anne Front Oncol Oncology We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-H3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201. Frontiers Media S.A. 2023-10-10 /pmc/articles/PMC10599138/ /pubmed/37886173 http://dx.doi.org/10.3389/fonc.2023.1229312 Text en Copyright © 2023 Menez, Kergrohen, Shasha, Silva-Evangelista, Le Dret, Auffret, Subecz, Lancien, Ajlil, Vilchis, Beccaria, Blauwblomme, Oberlin, Grill, Castel and Debily https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Menez, Virginie
Kergrohen, Thomas
Shasha, Tal
Silva-Evangelista, Claudia
Le Dret, Ludivine
Auffret, Lucie
Subecz, Chloé
Lancien, Manon
Ajlil, Yassine
Vilchis, Irma Segoviano
Beccaria, Kévin
Blauwblomme, Thomas
Oberlin, Estelle
Grill, Jacques
Castel, David
Debily, Marie-Anne
VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells
title VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells
title_full VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells
title_fullStr VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells
title_full_unstemmed VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells
title_short VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells
title_sort vrk3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - h3k27 altered cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599138/
https://www.ncbi.nlm.nih.gov/pubmed/37886173
http://dx.doi.org/10.3389/fonc.2023.1229312
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