| Literature DB >> 32859993 |
Fei Peng1,2, Jie Xu3, Bai Cui1, Qilan Liang1, Sai Zeng1, Bin He2, Hong Zou1, Manman Li1, Huan Zhao1, Yuting Meng1, Jin Chen4, Bing Liu1, Shasha Lv1, Peng Chu1,5, Fan An1, Zifeng Wang2, Junxiu Huang1, Yajing Zhan1, Yuwei Liao1, Jinxin Lu1, Lingzhi Xu6, Jin Zhang7, Zhaolin Sun5, Zhiguang Li1, Fangjun Wang4, Eric W-F Lam8, Quentin Liu9,10.
Abstract
RNase III DROSHA is upregulated in multiple cancers and contributes to tumor progression by hitherto unclear mechanisms. Here, we demonstrate that DROSHA interacts with β-Catenin to transactivate STC1 in an RNA cleavage-independent manner, contributing to breast cancer stem-like cell (BCSC) properties. DROSHA mRNA stability is enhanced by N6-methyladenosine (m6A) modification which is activated by AURKA in BCSCs. AURKA stabilizes METTL14 by inhibiting its ubiquitylation and degradation to promote DROSHA mRNA methylation. Moreover, binding of AURKA to DROSHA transcript further strengthens the binding of the m6A reader IGF2BP2 to stabilize m6A-modified DROSHA. In addition, wild-type DROSHA, but not an m6A methylation-deficient mutant, enhances BCSC stemness maintenance, while inhibition of DROSHA m6A modification attenuates BCSC traits. Our study unveils the AURKA-induced oncogenic m6A modification as a key regulator of DROSHA in breast cancer and identifies a novel DROSHA transcriptional function in promoting the BCSC phenotype.Entities:
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Year: 2020 PMID： 32859993 PMCID： PMC8027457 DOI： 10.1038/s41422-020-00397-2
Source DB: PubMed Journal: Cell Res ISSN： 1001-0602 Impact factor: 46.297