PDF(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.
摘要：
弥漫性内在脑桥胶质瘤（DIPG）是致命的小儿脑肿瘤，由于脑干定位和扩散生长而不可切除。超过80%的DIPG在组蛋白3(H3.3或H3.1)中具有突变,导致赖氨酸到甲硫氨酸的取代(H3K27M)。DIPG患者预后不佳，没有有效的治疗方法。我们表明，组蛋白去乙酰化酶（HDAC）抑制剂导致多种神经胶质瘤细胞系中H3.3K27M蛋白的显着减少（高达80％）。我们发现SB939介导的H3.3K27M损失被溶酶体抑制剂部分阻断，氯喹.H3.3K27M的损失是由H2A的共现促进的。Z,H2A的击倒证明了这一点。Z亚型。染色质免疫沉淀测序(ChIP-seq)分析证实了H3.3K27M和H2A的占有率。Z在相同的SB939诱导型基因上。我们发现了一种机制，表明DIPG中的HDAC抑制导致致癌H3.3K27M蛋白水平的药理学调节。这些发现显示了直接靶向H3.3K27M癌组蛋白的可能性。
