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

作者：Shiyan Wang, Shanshan Gao, Yong Zeng, Lin Zhu, Yulin Mo, Chi Chun Wong, Bao Yi, Peiran Su, Jianning Zhai, Lina Wang, Fraser Soares, Xin Xu, Huarong Chen, Kebria Hezaveh, Xinpei Ci, Aobo He, Tracy L. McGaha, Catherine O′Brien, Robert Rottapel, Wei Kang, Jianfeng Wu, Gang Zheng, Zongwei Cai, Jun Yu, Housheng Hansen He · 发表于：Gastroenterology · 年份：2021 · DOI：10.1053/j.gastro.2021.12.269 · 被引用次数：188 · 研究领域：RNA modifications and cancer、Epigenetics and DNA Methylation、Cancer-related gene regulation

Background & Aims N6-methyladenosine (m 6 A) governs the fate of RNAs through m 6 A readers. Colorectal cancer (CRC) exhibits aberrant m 6 A modifications and expression of m 6 A regulators. However, how m 6 A readers interpret oncogenic m 6 A 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, m 6 A 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-m 6 A-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 m 6 A sites of ARHGEF2 messenger RNA, resulting in enhanced translation of ARHGEF2 . Ectopic expression of ARHGEF...