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

作　　者：Fei Peng Jie Xu Bai Cui Qilan Liang Sai Zeng Bin He 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 Su Zhiguang Li Fangjun Wang Eric W-FLam Quentin Liu 

机构地区：[1]Institute of Cancer Stem Cell,Dalian Medical University,Dalian,Liaoning 116044,China [2]State Key Laboratory of Oncology in South China,Cancer Center,Sun Yat-sen University,Guangzhou,Guangdong 510060,China [3]Key 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 [4]Institute of Integrative Medicine,Dalian Medical University,Dalian,Liaoning 116044,China [5]Department of Oncology,the Second Affiliated Hospital,Dalian Medical University,Dalian,Liaoning 116023,China [6]The 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 [7]Department of Surgery and Cancer,Imperial College London,London,W120NN,UK

出　　处：《Cell Research》2021年第3期345-361,共17页细胞研究（英文版）

基　　金：supported by the National Key R&D Program of China(2019YFA0110300 to Q.Liu and 2017YFA0505600-04 to Q.Liu);the National Natural Science Foundation of China(81820108024 to Q.Liu,81630005 to Q.Liu,81972786 to J.X.,81573025 to Q.Liu,81703062 to L.H.and 81703091 to F.A.);Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China(IRT_17R15);Innovative Research Team in University of Liaoning(LT2017001 to Q.Liu);the Natural Science Foundation of Liaoning(2019-BS-081 to F.P.);the"Seedling cultivation"program for young scientific and technological talents of Liaoning(LZ2019067 to B.C.and 2020 to F.P.);the program for climbing Scholars of Liaoning,the Science and Technology Innovation Foundation of Dalian(2020JJ25CY008 to Q.Liu);Dalian High-level Talent Innovation Program(2016RD12 to Q.Liu);International Scientific and Technological Cooperation of Dalian(2015F11GH095 to Q.Liu);the Natural Science Foundation of Guangdong(2016A030311038 and 2017A030313608 to Q.Liu,2017A020215098 to Z.W.);the Science and Technology Planning Project of Guangzhou(201804020044 to Q.Liu);E.W-F.L/s work is supported by MRC(MR/N012097/1);CRUK(C37/A12011;C37/18784);Breast Cancer Now(2012MayPR070;,2012NovPhD016,2014NovPhD326)。

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 withβ-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(m^(6)A)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 m^(6)A reader IGF2BP2 to stabilize m^(6)A-modified DROSHA.In addition,wild-type DROSHA,but not an m^(6)A methylation-deficient mutant,enhances BCSC stemness maintenance,while inhibition of DROSHA m^(6)A modification attenuates BCSC traits.Our study unveils the AURKA-induced oncogenic m^(6)A modification as a key regulator of DROSHA in breast cancer and identifies a novel DROSHA transcriptional function in promoting the BCSC phenotype.

关 键 词：DROSHA AURKA BREAST 

分 类 号：R737.9[医药卫生—肿瘤]