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

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

  • Cell Res. 2021 Mar;31(3):345-361. doi: 10.1038/s41422-020-00397-2.
Fei Peng  # 1 2,  Jie Xu  # 3,  Bai Cui  # 1,  Qilan Liang  # 1,  Sai Zeng  # 1,  Bin He  # 2,  Hong Zou 1,  Manman Li 1,  Huan Zhao 1,  Yuting Meng 1,  Jin Chen 4,  Bing Liu 1,  Shasha Lv 1,  Peng Chu 1 5,  Fan An 1,  Zifeng Wang 2,  Junxiu Huang 1,  Yajing Zhan 1,  Yuwei Liao 1,  Jinxin Lu 1,  Lingzhi Xu 6,  Jin Zhang 7,  Zhaolin Sun 5,  Zhiguang Li 1,  Fangjun Wang 4,  Eric W-F Lam 8,  Quentin Liu 9 10
Affiliations

Affiliations

  • 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 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, 116044, China. [email protected].
  • 4 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.
  • 5 Institute of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, China.
  • 6 Department of Oncology, the Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116023, China.
  • 7 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.
  • 8 Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK.
  • 9 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning, 116044, China. [email protected].
  • 10 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China. [email protected].
  • # Contributed equally.
PMID: 32859993 DOI: 10.1038/s41422-020-00397-2
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.

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