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

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

Frontiers in oncology (2023-10-27)
Virginie Menez, Thomas Kergrohen, Tal Shasha, Claudia Silva-Evangelista, Ludivine Le Dret, Lucie Auffret, Chloé Subecz, Manon Lancien, Yassine Ajlil, Irma Segoviano Vilchis, Kévin Beccaria, Thomas Blauwblomme, Estelle Oberlin, Jacques Grill, David Castel, Marie-Anne Debily
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ro-31-8220, A cell-permeable, reversible, competitive, and selective inhibitor of protein kinase C (PKC; IC₅₀ = 10 nM) over CaM kinase II (IC₅₀ = 17 µM) and protein kinase A (IC₅₀ = 900 nM).