{Reference Type}: Journal Article
{Title}: H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in pediatric high-grade glioma cells.
{Author}: Leszczynska KB;Freitas-Huhtamäki A;Jayaprakash C;Dzwigonska M;Vitorino FNL;Horth C;Wojnicki K;Gielniewski B;Szadkowska P;Kaza B;Nazarian J;Ciolkowski MK;Trubicka J;Grajkowska W;Garcia BA;Majewski J;Kaminska B;Mieczkowski J;
{Journal}: Cell Rep
{Volume}: 43
{Issue}: 2
{Year}: 2024 Feb 27
暂无{DOI}: 10.1016/j.celrep.2024.113707
{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.