Oncogenic AURKA-enhanced N6-methyladenosine modification increases DROSHA mRNA stability to transactivate STCl in breast cancer stem-like cells

• 作者: Fei Peng Jie Xu Bai Cui Qilan Liang Sal Zeng Bin He2r Hong Zou Manman Li Huan Zhao Yuting Meng Jin Chen Bing Liu Shasha Lv Peng Chu Fan An Zifeng Wang Junxiu Huang Yajing Zhan Yuwei Liao Jinxin Lu Lingzhi Xu Jin Zhang Zhaolin Sun Zhiguang Li Fangjun Wang Eric W.-F. Lam Quentin Liu
• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: ARTICLES
• 页码范围: 345-361
• 页数: 17页
• 语种: 英文

摘要

RNase Ⅲ DROSHA is upregulated in multiple cancers and contributes to tumor progression by hitherto unclear mechanisms.Here,we demonstrate that DROSHA interacts with p-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 DR05HA m6A modification attenuates BCSC traits.Our study unveils the AURKA-induced oncogenic m6A modification as a key regulator of DR05HA in breast cancer and identifies a novel DROSHA transcriptional function in promoting the BCSC phenotype.