Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Rep. 2022 Oct 25;41(4):111530. doi: 10.1016/j.celrep.2022.111530.
SHH subgroup medulloblastoma (SHH-MB) is one of the most common malignant pediatric tumors that arises in the cerebellum. Previously, we showed that RNA mA methylation participates in regulation of cerebellar development. Here we investigate whether dysregulated mA methylation contributes to tumorigenesis of SHH-MB. We show that high expression of mA methyltransferase METTL3 associates with worse survival in the patients with SHH-MB. A large number of hypermethylated transcripts are identified in SHH-MB tumor cells by mA-seq. We find that METTL3 promotes tumor progression via activating Sonic hedgehog signaling. Mechanistically, METTL3 methylates PTCH1 and GLI2 RNAs and further regulates their RNA stability and translation. Importantly, targeting METTL3 by depleting METTL3 expression or treatment with its catalytic inhibitor STM2457 restrains tumor progression. Collectively, this study shows a critical function for METTL3 and mA methylation in SHH-MB, indicative of a potential role of METTL3 as therapeutic target in SHH-MB.
SHH 亚型髓母细胞瘤（SHH-MB）是一种最常见的起源于小脑的小儿恶性肿瘤。此前，我们发现 RNA mA 甲基化参与小脑发育的调控。在此，我们研究了失调的 mA 甲基化是否有助于 SHH-MB 的肿瘤发生。我们发现，mA 甲基转移酶 METTL3 的高表达与 SHH-MB 患者的生存预后不良相关。通过 mA-seq 在 SHH-MB 肿瘤细胞中鉴定到大量高甲基化的转录本。我们发现 METTL3 通过激活 Sonic hedgehog 信号促进肿瘤进展。在机制上，METTL3 甲基化 PTCH1 和 GLI2 的 RNA，并进一步调节它们的 RNA 稳定性和翻译。重要的是，通过耗尽 METTL3 表达或用其催化抑制剂 STM2457 处理来靶向 METTL3 可抑制肿瘤进展。总之，这项研究表明 METTL3 和 mA 甲基化在 SHH-MB 中具有关键功能，提示 METTL3 作为 SHH-MB 的治疗靶点具有潜在作用。
