Medulloblastoma, a highly malignant pediatric brain tumor, consists of four molecular subgroups, namely WNT, SHH, Group 3, and Group 4. The expression of miR-193a, a WNT subgroup-specific microRNA, was found to be induced by MYC, an oncogenic target of the canonical WNT signaling. MiR-193a is not expressed in Group 3 medulloblastomas, despite MYC expression, as a result of promoter hypermethylation. Restoration of miR-193a expression in the MYC amplified Group 3 medulloblastoma cells resulted in inhibition of growth, tumorigenicity, and an increase in radiation sensitivity. MAX, STMN1, and DCAF7 were identified as novel targets of miR-193a. MiR-193a mediated downregulation of MAX could suppress MYC activity since it is an obligate hetero-dimerization partner of MYC. MYC induced expression of miR-193a, therefore, seems to act as a feedback inhibitor of MYC signaling. The expression of miR-193a resulted in widespread repression of gene expression that included not only several cell cycle regulators, WNT, NOTCH signaling genes, and those encoding DNA replication machinery, but also several chromatin modifiers like SWI/SNF family genes and histone-encoding genes. MiR-193a expression brought about a reduction in the global levels of H3K4me3, H3K27ac, the histone marks of active chromatin, and an increase in the levels of H3K27me3, a repressive chromatin mark. In cancer cells having high MYC expression, MYC brings about transcriptional amplification of all active genes apart from the induction of its target genes. MiR-193a, on the other hand, brought about global repression of gene expression. Therefore, miR-193a has therapeutic potential in the treatment of not only Group 3 medulloblastomas but possibly other MYC overexpressing aggressive cancers as well.

中文翻译：

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在MYC扩增的第3组髓母细胞瘤中，miR-193a表达的恢复具有肿瘤抑制作用。

髓母细胞瘤是一种高度恶性的小儿脑肿瘤，由四个分子亚组组成，即WNT，SHH，第3组和第4组。发现miR-193a（一种WNT亚组特异性microRNA）的表达被MYC诱导。经典WNT信号的致癌靶标。尽管MYC表达，但由于启动子高甲基化，MiR-193a在第3组髓母细胞瘤中不表达。在MYC扩增的第3组髓母细胞瘤细胞中miR-193a表达的恢复导致生长抑制，致瘤性和放射敏感性增加。MAX，STMN1和DCAF7被鉴定为miR-193a的新型靶标。MiR-193a介导的MAX下调可以抑制MYC活性，因为它是MYC的专职异二聚体伴侣。MYC诱导miR-193a的表达，因此，似乎是MYC信号的反馈抑制剂。miR-193a的表达导致基因表达的广泛抑制，不仅包括几个细胞周期调节子，WNT，NOTCH信号基因和那些编码DNA复制机制的基因，还包括一些染色质修饰剂，例如SWI / SNF家族基因和组蛋白编码基因。MiR-193a表达导致活性染色质的组蛋白标记H3K4me3，H3K27ac的总体水平降低，以及抑制性染色质标记的H3K27me3的水平升高。在具有高MYC表达的癌细胞中，MYC除了诱导其靶基因外，还引起所有活性基因的转录扩增。另一方面，MiR-193a引起了基因表达的整体抑制。因此，