Department of Pediatrics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
Department of Pediatrics, Children's Memorial Hospital, Northwestern University and the Feinberg School of Medicine, Chicago, IL, USA.
Mol Cancer Ther. 2012 Aug;11(8):1713-1723. doi: 10.1158/1535-7163.MCT-11-0990. Epub 2012 Jul 30.
Medulloblastoma is a malignant pediatric brain tumor. Current treatment following patient stratification into standard and high-risk groups using clinical features has improved survival. However, a subset of patients with standard risk features have unanticipated aggressive disease, underscoring the need for a better understanding of tumor biology and the development of novel treatments. Poor differentiation, a hallmark of medulloblastomas is associated with elevated expression levels of the repressor of neuronal differentiation called repressor element 1-silencing transcription factor (REST). Here, we assessed whether elevated REST expression levels had prognostic significance and whether its pharmacologic manipulation would promote neurogenesis and block tumor cell growth. REST levels in patient tumors were measured by immunohistochemistry and stratified into negative, low/moderate- (+/++/+++), and high-REST (+++++) groups. Kaplan-Meier curves revealed that patients with high-REST tumors had worse overall and event-free survival compared with patients with REST-negative or REST-low tumors. Because histone deacetylases (HDAC) are required for REST-dependent repression of neurogenesis, we evaluated a panel of HDAC inhibitors (HDACI) for their effects on growth and differentiation of established and primary REST-positive cell lines. MS-275, trichostatin-A (TSA), valproic acid (VPA), and suberoylanilide hydroxamic acid (SAHA) upregulated expression of the REST-target neuronal differentiation gene, Syn1, suggesting a potential effect of these HDACIs on REST function. Interestingly, VPA and TSA substantially increased histone acetylation at the REST promoter and activated its transcription, whereas SAHA unexpectedly promoted its proteasomal degradation. A REST-dependent decrease in cell growth was also observed following SAHA treatment. Thus, our studies suggest that HDACIs may have therapeutic potential for patients with REST-positive tumors. This warrants further investigation.
髓母细胞瘤是一种恶性小儿脑肿瘤。目前，根据临床特征将患者分层为标准风险组和高风险组后进行治疗，已提高了生存率。然而，一部分具有标准风险特征的患者出现了意料之外的侵袭性疾病，这突显了需要更好地了解肿瘤生物学并开发新的治疗方法。分化不良是髓母细胞瘤的一个标志，与神经元分化抑制剂 repressor element 1-silencing transcription factor (REST) 的表达水平升高有关。在这里，我们评估了 REST 表达水平是否具有预后意义，以及其药物处理是否会促进神经发生并阻止肿瘤细胞生长。通过免疫组织化学测量患者肿瘤中的 REST 水平，并将其分为阴性、低/中- (+/++/+++) 和高-REST (+++++) 组。Kaplan-Meier 曲线显示，高-REST 肿瘤患者的总生存率和无事件生存率均比 REST 阴性或 REST 低肿瘤患者差。由于组蛋白去乙酰化酶 (HDAC) 是 REST 依赖性抑制神经发生所必需的，因此我们评估了一组 HDAC 抑制剂 (HDACI) 对已建立的和原发性 REST 阳性细胞系的生长和分化的影响。MS-275、曲古抑菌素 A (TSA)、丙戊酸 (VPA) 和 suberoylanilide hydroxamic acid (SAHA) 上调了 REST 靶神经元分化基因 Syn1 的表达，表明这些 HDACIs 可能对 REST 功能具有潜在影响。有趣的是，VPA 和 TSA 显著增加了 REST 启动子处的组蛋白乙酰化并激活其转录，而 SAHA 出人意料地促进了其蛋白酶体降解。SAHA 处理后还观察到细胞生长的 REST 依赖性下降。因此，我们的研究表明，HDACIs 可能对 REST 阳性肿瘤患者具有治疗潜力。这需要进一步研究。
