Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin
Epigenetic upregulation of Schlafen11 renders WNT- and SHH-activated medulloblastomas sensitive to cisplatin
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Schlafen11 的表观遗传上调使 WNT 和 SHH 激活的髓母细胞瘤对顺铂敏感
DOI：
10.1093/neuonc/noac243
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发表时间：
2022
期刊：
影响因子：
15.9
通讯作者：
Natsumeda Manabu
中科院分区：
文献类型：
--
作者：
Nakata Satoshi;Murai Junko;Okada Masayasu,,,,,Tateishi Kensuke;Yamashita Shinji;Eberhart Charles G;Natsumeda Manabu
背景：强化化疗联合全脑脊髓照射能显著提高髓母细胞瘤患者的生存率。然而，分子亚组之间的生存率显着不同，其生物标志物是未知的。通过无偏筛选，我们发现Schlafen家族成员11（SLFN 11）是髓母细胞瘤的最佳预后标志物之一，已知其可改善各种癌症对DNA损伤剂的反应。方法采用免疫组织化学方法检测98例髓母细胞瘤患者的SLFN 11表达，并分析转录组学数据。我们遗传或表观遗传调制SLFN 11在髓母细胞瘤细胞系的表达和确定的DNA损伤剂顺铂和拓扑异构酶I抑制剂SN-38在体外和体内的细胞毒性反应。SLFN 11在WNT激活亚组和SHH激活亚组中高度表达。虽然WNT激活不是SLFN 11高表达的直接原因，但SLFN 11启动子上的特定低甲基化位点与SLFN 11高表达显著相关。SLFN 11的过表达或缺失分别使髓母细胞瘤细胞对顺铂和SN-38敏感和耐药。脑渗透性组蛋白去乙酰化酶抑制剂RG 2833对SLFN 11的药理学上调显著增加了SLFN 11阴性髓母细胞瘤细胞对顺铂和SN-38的敏感性。颅内异种移植物的研究也显示了显着的敏感性顺铂SLFN 11-过表达在髓母细胞瘤cells.ConclusionsHigh SLFN 11的表达是一个因素，使WNT激活和一个子集的SHH激活髓母细胞瘤可能通过增强对顺铂的反应有利的结果。
BackgroundIntensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma.MethodsSLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo.ResultsHigh SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on theSLFN11promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion ofSLFN11made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells.ConclusionsHigh SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.