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N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer.
Wang, Shiyan; Gao, Shanshan; Zeng, Yong; Zhu, Lin; Mo, Yulin; Wong, Chi Chun; Bao, Yi; Su, Peiran; Zhai, Jianning; Wang, Lina; Soares, Fraser; Xu, Xin; Chen, Huarong; Hezaveh, Kebria; Ci, Xinpei; He, Aobo; McGaha, Tracy; O'Brien, Catherine; Rottapel, Robert; Kang, Wei; Wu, Jianfeng; Zheng, Gang; Cai, Zongwei; Yu, Jun; He, Housheng Hansen.
Afiliação
  • Wang S; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.
  • Gao S; Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • Zeng Y; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.
  • Zhu L; State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
  • Mo Y; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
  • Wong CC; Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • Bao Y; Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • Su P; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Zhai J; Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • Wang L; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangdong, China.
  • Soares F; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.
  • Xu X; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.
  • Chen H; Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
  • Hezaveh K; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.
  • Ci X; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.
  • He A; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • McGaha T; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada.
  • O'Brien C; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Rottapel R; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Kang W; Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • Wu J; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
  • Zheng G; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Cai Z; State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
  • Yu J; Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: junyu@cuhk.edu.hk.
  • He HH; Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Electronic address: hansenhe@uhnresearch.ca.
Gastroenterology ; 162(4): 1183-1196, 2022 04.
Article em En | MEDLINE | ID: mdl-34968454
ABSTRACT
BACKGROUND &

AIMS:

N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, how m6A readers interpret oncogenic m6A methylome to promote malignant transformation remains to be illustrated.

METHODS:

YTH N6-methyladenosine RNA binding protein 1 (Ythdf1) knockout mouse was generated to determine the effect of Ythdf1 in CRC tumorigenesis in vivo. Multiomic analysis of RNA-sequencing, m6A methylated RNA immunoprecipitation sequencing, YTHDF1 RNA immunoprecipitation sequencing, and proteomics were performed to unravel targets of YTHDF1 in CRC. The therapeutic potential of targeting YTHDF1-m6A-Rho/Rac guanine nucleotide exchange factor 2 (ARHGEF2) was evaluated using small interfering RNA (siRNA) encapsulated by lipid nanoparticles (LNP).

RESULTS:

DNA copy number gain of YTHDF1 is a frequent event in CRC and contributes to its overexpression. High expression of YTHDF1 is significantly associated with metastatic gene signature in patient tumors. Ythdf1 knockout in mice dampened tumor growth in an inflammatory CRC model. YTHDF1 promotes cell growth in CRC cell lines and primary organoids and lung and liver metastasis in vivo. Integrative multiomics analysis identified RhoA activator ARHGEF2 as a key downstream target of YTHDF1. YTHDF1 binds to m6A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2. Ectopic expression of ARHGEF2 restored impaired RhoA signaling, cell growth, and metastatic ability both in vitro and in vivo caused by YTHDF1 loss, verifying that ARHGEF2 is a key target of YTHDF1. Finally, ARHGEF2 siRNA delivered by LNP significantly suppressed tumor growth and metastasis in vivo.

CONCLUSIONS:

We identify a novel oncogenic epitranscriptome axis of YTHDF1-m6A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Regulação Neoplásica da Expressão Gênica Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Gastroenterology Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Regulação Neoplásica da Expressão Gênica Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Gastroenterology Ano de publicação: 2022 Tipo de documento: Article