Volume 31, No 3, Mar 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 3, March 2021: 345-361

ORIGINAL ARTICLES

Oncogenic AURKA-enhanced N6-methyladenosine modification increases DROSHA mRNA stability to transactivate STC1 in breast cancer stem-like cells

Fei Peng^1,2 , Jie Xu^1,* , Bai Cui¹ , Qilan Liang¹ , Sai Zeng¹ , Bin He² , Hong Zou¹ , Manman Li¹ , Huan Zhao¹ , Yuting Meng¹ , Jin Chen³ , Bing Liu¹ , Shasha Lv¹ , Peng Chu^1,4 , Fan An¹ , Zifeng Wang² , Junxiu Huang¹ , Yajing Zhan¹ , Yuwei Liao¹ , Jinxin Lu¹ , Lingzhi Xu⁵ , Jin Zhang⁶ , Zhaolin Su⁴ , Zhiguang Li¹ , Fangjun Wang³ , Eric W.-F. Lam⁷ , Quentin Liu^1,2,*

¹Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China
²State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
³Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian, Liaoning 116023, China
⁴Institute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning 116044, China
⁵Department of Oncology, the Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116023, China
⁶The 3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, Tianjin 300060, China
⁷Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK
These authors contributed equally: Fei Peng, Jie Xu, Bai Cui, Qilan Liang, Sai Zeng, Bin He Correspondence: Jie Xu(xujie@dmu.edu.cn)Quentin Liu(liuq9@mail.sysu.edu.cn)

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.

https://doi.org/10.1038/s41422-020-00397-2

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