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

被引：50

作者：

Zhang, Zhi-Wei ^{[1
]}

Teng, Xufei ^{[2
,5
]}

Zhao, Fu ^{[3
,4
]}

Ma, Chunhui ^{[1
]}

Zhang, Jing ^{[3
]}

Xiao, Ling-Feng ^{[1
]}

Wang, Yaning ^{[6
]}

Chang, Mengqi ^{[1
]}

Tian, Yongji ^{[4
]}

Li, Chunde ^{[3
,4
]}

Zhang, Zhang ^{[2
,5
]}

Song, Shuhui ^{[2
,5
]}

Tong, Wei-Min ^{[1
,7
]}

Liu, Pinan ^{[3
,4
]}

Niu, Yamei ^{[1
,7
]}

机构：

[1] Chinese Acad Med Sci, Peking Union Med Coll, Inst Basic Med Sci, Sch Basic Med,Neurosci Ctr,Dept Pathol, Beijing 100005, Peoples R China

[2] Chinese Acad Sci, Beijing Inst Genom, China Natl Ctr Bioinformat, Natl Genom Data Ctr, Beijing 100101, Peoples R China

[3] Capital Med Univ, Beijing Neurosurg Inst, Dept Neural Reconstruct, Beijing 100070, Peoples R China

[4] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurosurg, Beijing 100070, Peoples R China

[5] Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China

[6] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Neurosurg, Beijing 100730, Peoples R China

[7] Chinese Acad Med Sci & Peking Union Med Coll, Mol Pathol Res Ctr, Beijing 100730, Peoples R China

来源：

CELL REPORTS | 2022年 / 41卷 / 03期

基金：

北京市自然科学基金; 国家重点研发计划; 中国国家自然科学基金;

关键词：

DNA METHYLATION; PATHWAY; TRANSLATION; CANCER; DEMETHYLASE; SUBGROUPS; LANDSCAPE; GENES; RNAS;

D O I：

10.1016/j.celrep.2022.111530

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 cere-bellar development. Here we investigate whether dysregulated m6A methylation contributes to tumorigen-esis of SHH-MB. We show that high expression of m6A methyltransferase METTL3 associates with worse sur-vival 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 sta-bility 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.

引用

页数：26

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