N6-Methyladenosine Reader YTHDF1 Promotes ARHGEF2 Translation and RhoA Signaling in Colorectal Cancer
Year: 2021
Type: article
Abstract: 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 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-m 6 A-ARHGEF2, which regulates CRC tumorigenesis and metastasis. siRNA-delivering LNP drug validated the therapeutic potential of targeting this axis in CRC.
Source: Gastroenterology
Authors: 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 Kang, Jianfeng Wu, Gang Zheng, Zongwei Cai, Jun Yu, Housheng Hansen He
Institutions: University Health Network, Princess Margaret Cancer Centre, Chinese University of Hong Kong, Chinese University of Hong Kong, Shenzhen, Hong Kong Baptist University, State Key Laboratory of Environmental and Biological Analysis, University of Toronto, The First Affiliated Hospital, Sun Yat-sen University, Prince of Wales Hospital, State Key Laboratory of Oncology in South China, Xiamen University, State Key Laboratory of Cell Stress Biology
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,200
OpenAlex ID: W4200260682