N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer

Shiyan Wang, Shanshan Gao, Yong Zeng, Lin Zhu, Yulin Mo, Chi Chun Wong, Yi Bao, Peiran Su, Jianning Zhai, Lina Wang, Fraser Soares, Xin Xu, Huarong Chen, Kebria Hezaveh, Xinpei Ci, Aobo He, Tracy McGaha, Catherine O'Brien, Robert Rottapel, Wei KangJianfeng Wu, Gang Zheng, Zongwei Cai, Jun Yu*, Housheng Hansen He*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

89 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1183-1196
Number of pages14
JournalGastroenterology
Volume162
Issue number4
DOIs
Publication statusPublished - Apr 2022

Scopus Subject Areas

  • Gastroenterology
  • Hepatology

User-Defined Keywords

  • ARHGEF2
  • Colorectal Cancer
  • N6-Methyladenosine
  • Nanoparticle
  • YTHDF1
  • rhoA GTP-Binding Protein/genetics
  • Colorectal Neoplasms/pathology
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Rho Guanine Nucleotide Exchange Factors/genetics
  • RNA-Binding Proteins/genetics
  • Nanoparticles
  • Adenosine/analogs & derivatives
  • Animals
  • Mice
  • RNA, Small Interfering
  • Liposomes
  • Carcinogenesis/genetics

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