METTL3 regulates m6A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma

SHH subgroup medulloblastoma (SHH-MB) is one of the most common malignant pediatric tumors that arises in the cerebellum. Previously, we showed that RNA m6A methylation participates in regulation of cerebellar development. Here we investigate whether dysregulated m6A methylation contributes to tumorigenesis of SHH-MB. We show that high expression of m6A 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 m6A-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 m6A methylation in SHH-MB, indicative of a potential role of METTL3 as therapeutic target in SHH-MB. [Display omitted] •Overexpression of METTL3 correlates with worse prognosis in SHH-MB•SHH-MB tumors exhibit significant RNA m6A hypermethylation•METTL3 predominantly regulates PTCH1 and GLI2 RNA methylation in hedgehog signaling•Targeting METTL3 inhibits tumor growth of SHH-MB Zhang et al. show that SHH-MB exhibits RNA m6A hypermethylation compared with normal cerebella. Overexpression of m6A methyltransferase METTL3 causes hypermethylation of PTCH1 and GLI2, as well as sustained hedgehog signaling, which further promotes tumor progression of SHH-MB. Targeting METTL3 could inhibit tumor growth, suggesting a potential therapeutic strategy of SHH-MB.