Department of Pediatrics, University of Texas M.D. Anderson Cancer Center, Unit 853, 1515 Holcombe Blvd, Houston, TX, 77030, USA.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Austin, USA.
Cell Commun Signal. 2018 Sep 18;16(1):60. doi: 10.1186/s12964-018-0275-5.
Medulloblastoma (MB) is the most common malignant brain tumor in children. Current problems in the clinic include metastasis, recurrence, and treatment-related sequelae that highlight the need for targeted therapies. Epigenetic perturbations are an established hallmark of human MB and expression of Lysine Specific Demethylase 1 (LSD1) is elevated in MBs compared to normal tissue, suggesting that LSD1 inhibitors may have efficacy against human MB tumors.
Expression of LSD1 was examined across a publicly-available database and correlated with patient outcomes. Sonic Hedgehog (SHH) MB samples were clustered based on expression of LSD1 and LSD1-associated RE-1 silencing transcription factor (REST) target genes as well as genes involved in metastasis. Resulting clusters were examined for patient outcomes associated with LSD1 and REST expression. Human SHH MB cell lines were transduced with a REST-transgene to create isogenic cell pairs. In vitro viability and cell migration assays were used to examine the effect of LSD1 knockdown or inhibition on these parameters.
We demonstrate that subsets of SHH MB tumors have elevated LSD1 expression coincident with increased expression of its deubiquitylase, USP7, and REST. Patients with co-elevation of USP7, REST, and LSD1 have poorer outcomes compared to those with lower expression of these genes. In SHH MB cell lines, REST elevation increased cell growth and LSD1 protein levels. Surprisingly, while genetic loss of LSD1 reduced cell viability, pharmacological targeting of its activity using LSD1 inhibitors did not affect cell viability. However, a reduction in REST-dependent cell migration was seen in wound healing, suggesting that REST-LSD1 interaction regulates cell migration. Ingenuity pathway analyses validated these findings and identified Hypoxia Inducible Factor 1 alpha (HIF1A) as a potential target. In line with this, ectopic expression of HIF1A rescued the loss of migration seen following LSD1 inhibition.
A subset of SHH patients display increased levels of LSD1 and REST, which is associated with poor outcomes. REST elevation in MB in conjunction with elevated LSD1 promotes MB cell migration. LSD1 inhibition blocks REST-dependent cell migration of MB cells in a HIF1A-dependent manner.
髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤。目前临床上存在的问题包括转移、复发和与治疗相关的后遗症，这突出表明需要进行靶向治疗。表观遗传扰动是人类 MB 的一个既定标志，与正常组织相比，赖氨酸特异性去甲基酶 1（LSD1）在 MB 中表达升高，这表明 LSD1 抑制剂可能对人类 MB 肿瘤有效。
在公开数据库中检查 LSD1 的表达，并与患者的预后相关联。根据 LSD1 和 LSD1 相关的 RE-1 沉默转录因子（REST）靶基因以及与转移相关的基因，对 Sonic Hedgehog（SHH）MB 样本进行聚类。对与 LSD1 和 REST 表达相关的患者结果进行检查。用 REST 转染基因转导人类 SHH MB 细胞系，以创建同基因细胞对。体外活力和细胞迁移测定用于研究 LSD1 敲低或抑制对这些参数的影响。
我们证明，SHH MB 肿瘤的亚组具有 LSD1 表达升高，同时其去泛素酶 USP7 和 REST 表达升高。USP7、REST 和 LSD1 共同升高的患者与这些基因表达较低的患者相比，预后较差。在 SHH MB 细胞系中，REST 升高增加了细胞生长和 LSD1 蛋白水平。令人惊讶的是，虽然 LSD1 的遗传缺失降低了细胞活力，但使用 LSD1 抑制剂对其活性进行药理学靶向治疗并不影响细胞活力。然而，在创伤愈合中观察到 REST 依赖性细胞迁移减少，表明 REST-LSD1 相互作用调节细胞迁移。通路分析验证了这些发现，并确定缺氧诱导因子 1 阿尔法（HIF1A）为潜在靶点。与此一致，HIF1A 的异位表达挽救了 LSD1 抑制后观察到的迁移损失。
SHH 患者的亚组表现出 LSD1 和 REST 水平升高，这与不良预后相关。MB 中 REST 的升高与 LSD1 的升高一起促进了 MB 细胞的迁移。LSD1 抑制以 HIF1A 依赖的方式阻断 MB 细胞中 REST 依赖性细胞迁移。
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