MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation
MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation
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DOI：
10.1158/1541-7786.mcr-17-0105
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发表时间：
2017-09-01
影响因子：
5.2
通讯作者：
Gu, Chunyu
中科院分区：
文献类型：
--
作者：
Liu, Hailong;Sun, Qianwen;Gu, Chunyu
髓母细胞瘤是儿童最常见的恶性脑肿瘤。虽然累积的研究表明，肿瘤干细胞样细胞在髓母细胞瘤的肿瘤发生中起着关键作用，关于增殖的具体分子机制仍然是难以捉摸的。在此，我们报道了母胚亮氨酸拉链激酶（MELK）和zeste同源物增强子2（EZH 2）在髓母细胞瘤干细胞样细胞中比在神经干细胞中更丰富的表达，并且这两种蛋白之间的相互作用可以介导音刺猬亚型髓母细胞瘤的自我更新。在人髓母细胞瘤中，广泛结节化和大细胞/间变性亚组根据MELK和EZH 2的染色水平与其他两个亚组不同。MEL K或EZH 2阳性染色状态的比例可被认为是存活的潜在指标。在机制上，MELK与EZH 2结合并磷酸化，并且其甲基化被髓母细胞瘤中的EZH 2诱导，这可以调节癌症干细胞样细胞的增殖。在异种移植物中，MELK或EZH 2的缺失减弱了髓母细胞瘤干细胞样细胞衍生的肿瘤生长并促进了分化。这些发现表明MELK/EZH 2通路中MEK诱导的磷酸化和EZH 2介导的甲基化对于髓母细胞瘤干细胞样细胞衍生的肿瘤增殖是必不可少的，从而为这些患者确定了潜在的治疗策略。这项研究表明，MELK和EZH 2之间发生的相互作用促进了自我增殖和干性，因此代表了用于诊断髓母细胞瘤的有吸引力的治疗靶点和潜在候选物。(C)2017年AACR。
Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK-or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stem-like cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma. (C) 2017 AACR.