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

Francisca N L Vitorino, Jakub Mieczkowski, Wieslawa Grajkowska, Maciej K Ciolkowski, Beata Kaza, Paulina Szadkowska, Bartlomiej Gielniewski, Kamil Wojnicki, Cynthia Horth, Bozena Kaminska, Monika Dzwigonska, Amanda Freitas-Huhtamäki, Katarzyna B Leszczynska, Benjamin A Garcia, Joanna Trubicka, Chinchu Jayaprakash, Jacek Majewski, Javad Nazarian

Journal: Cell reports 2024;43(2):113707

PMID: 38306270

Free Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland. Electronic address: [email protected].; Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.; Department of Human Genetics, McGill University, Montreal, QC, Canada.; Center for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, University Children's Hospital Zürich, Zürich, Switzerland.; Children's Memorial Health Institute, Warsaw, Poland.; Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland; 3P-Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2024.113707

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/braintumors.html

Miscellaneous:

https://assays.cancer.gov/CPTAC-660

Molecular Biology Databases:

https://data.niaid.nih.gov/resources?id=gse232283

MeSH Terms: Humans, Child, Histones, Mutant Proteins, Glioma, Diffuse Intrinsic Pontine Glioma, Brain Neoplasms, Histone Deacetylase Inhibitors