%0 Journal Article
%T H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells.
%A Leszczynska KB
%A Freitas-Huhtamäki A
%A Jayaprakash C
%A Dzwigonska M
%A Vitorino FNL
%A Horth C
%A Wojnicki K
%A Gielniewski B
%A Szadkowska P
%A Kaza B
%A Nazarian J
%A Ciolkowski MK
%A Trubicka J
%A Grajkowska W
%A Garcia BA
%A Majewski J
%A Kaminska B
%A Mieczkowski J
%J Cell Rep
%V 43
%N 2
%D 2024 Feb 27
%M 38306270
暂无%R 10.1016/j.celrep.2024.113707
%X 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.