H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells

• Published in: Cell reports (Cambridge) Vol. 43; no. 2; p. 113707
• Main Authors: Leszczynska, Katarzyna B., Freitas-Huhtamäki, Amanda, Jayaprakash, Chinchu, Dzwigonska, Monika, Vitorino, Francisca N.L., Horth, Cynthia, Wojnicki, Kamil, Gielniewski, Bartlomiej, Szadkowska, Paulina, Kaza, Beata, Nazarian, Javad, Ciolkowski, Maciej K., Trubicka, Joanna, Grajkowska, Wieslawa, Garcia, Benjamin A., Majewski, Jacek, Kaminska, Bozena, Mieczkowski, Jakub
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.02.2024; Elsevier
• Subjects: Brain Neoplasms - genetics; Child; CP: Cancer; Diffuse Intrinsic Pontine Glioma; DIPG; Glioma - genetics; H2A.Z; H3.3; H3.3K27M; HDAC inhibitors; Histone Deacetylase Inhibitors - pharmacology; histone variants; Histones; Humans; multiomics; Mutant Proteins; pediatric high-grade gliomas; SB939; SB939; H3.3; histone variants; CP: Cancer; pediatric high-grade gliomas; HDAC inhibitors; multiomics; DIPG; H2A.Z; H3.3K27M
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113707

Diffuse intrinsic pontine gliomas (DIPGs) are deadly pediatric brain tumors, non-resectable due to brainstem localization and diffusive growth. Over 80% of DIPGs harbor a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine-to-methionine substitution (H3K27M). Patients with DIPG have a dismal prognosis with no effective therapy. We show that histone deacetylase (HDAC) inhibitors lead to a significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines. We discover that the SB939-mediated H3.3K27M loss is partially blocked by a lysosomal inhibitor, chloroquine. The H3.3K27M loss is facilitated by co-occurrence of H2A.Z, as evidenced by the knockdown of H2A.Z isoforms. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. We discover a mechanism showing that HDAC inhibition in DIPG leads to pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings show the possibility of directly targeting the H3.3K27M oncohistone. [Display omitted] •HDAC inhibitors (SB939, panobinostat, vorinostat, entinostat) decrease H3K27M protein levels•HDACi-induced loss of H3K27M is prevented via a chloroquine-dependent mechanism•Presence of H2A.Z facilitates the HDACi-induced loss of H3K27M oncohistone•The loss of H2A.Z and H3K27M co-occurs at the same HDACi-inducible genes Leszczynska et al. show that the H3K27M oncohistone, the oncogenic driver of pediatric H3K27-altered diffuse midline gliomas, is decreased at the protein level in response to HDAC inhibition. They show that this disease-specific consequence of HDAC inhibition is modulated via the action of chloroquine and H2A.Z histone variants.