Department of Pediatric Oncology and Hematology, University Hospital Essen, Essen, Germany.
Acta Neuropathol Commun. 2013 May 29;1:19. doi: 10.1186/2051-5960-1-19.
Medulloblastoma is a leading cause of childhood cancer-related deaths. Current aggressive treatments frequently lead to cognitive and neurological disabilities in survivors. Novel targeted therapies are required to improve outcome in high-risk medulloblastoma patients and quality of life of survivors. Targeting enzymes controlling epigenetic alterations is a promising approach recently bolstered by the identification of mutations in histone demethylating enzymes in medulloblastoma sequencing efforts. Hypomethylation of lysine 4 in histone 3 (H3K4) is also associated with a dismal prognosis for medulloblastoma patients. Functional characterization of important epigenetic key regulators is urgently needed.
We examined the role of the H3K4 modifying enzyme, KDM1A, in medulloblastoma, an enzyme also associated with malignant progression in the closely related tumor, neuroblastoma. Re-analysis of gene expression data and immunohistochemistry of tissue microarrays of human medulloblastomas showed strong KDM1A overexpression in the majority of tumors throughout all molecular subgroups. Interestingly, KDM1A knockdown in medulloblastoma cell lines not only induced apoptosis and suppressed proliferation, but also impaired migratory capacity. Further analyses revealed bone morphogenetic protein 2 (BMP2) as a major KDM1A target gene. BMP2 is known to be involved in development and differentiation of granule neuron precursor cells (GNCPs), one potential cell of origin for medulloblastoma. Treating medulloblastoma cells with the specific KDM1A inhibitor, NCL-1, significantly inhibited growth in vitro.
We provide the first evidence that a histone demethylase is functionally involved in the regulation of the malignant phenotype of medulloblastoma cells, and lay a foundation for future evaluation of KDM1A-inihibiting therapies in combating medulloblastoma.
髓母细胞瘤是导致儿童癌症相关死亡的主要原因。目前，积极的治疗方法经常导致幸存者出现认知和神经功能障碍。需要新的靶向治疗方法来改善高危髓母细胞瘤患者的预后和幸存者的生活质量。靶向控制表观遗传改变的酶是一种很有前途的方法，最近通过在髓母细胞瘤测序工作中鉴定组蛋白去甲基化酶的突变得到了加强。组蛋白 3（H3）赖氨酸 4 的低甲基化与髓母细胞瘤患者的预后不良相关。迫切需要对重要的表观遗传关键调节因子进行功能特征分析。
我们研究了 H3K4 修饰酶 KDM1A 在髓母细胞瘤中的作用，该酶也与密切相关的肿瘤神经母细胞瘤中的恶性进展有关。对人类髓母细胞瘤的基因表达数据和组织微阵列免疫组织化学的重新分析表明，大多数肿瘤中 KDM1A 过表达存在于所有分子亚群中。有趣的是，KDM1A 在髓母细胞瘤细胞系中的敲低不仅诱导了细胞凋亡和抑制了增殖，还损害了迁移能力。进一步的分析显示骨形态发生蛋白 2（BMP2）是 KDM1A 的主要靶基因。BMP2 已知参与颗粒神经元前体细胞（GNCPs）的发育和分化，GNCPs 是髓母细胞瘤的一个潜在起源细胞。用特异性 KDM1A 抑制剂 NCL-1 处理髓母细胞瘤细胞，显著抑制了体外生长。
我们首次提供了证据，证明组蛋白去甲基酶在调节髓母细胞瘤细胞的恶性表型方面具有功能作用，并为未来评估 KDM1A 抑制治疗在对抗髓母细胞瘤中的作用奠定了基础。
