Downregulation of the m6A reader YTHDC2 upregulates exosome content in lung adenocarcinoma via inhibiting IFIT and OAS family members

Zhixin Yin; Lifang Ma; Xiaoting Tian; Qi Sun; Congcong Zhang; Yikun Wang; Yayou Miao; Xiangfei Xue; Yongjie Wang; Jiayi Wang; Xiao Zhang; Xumin Hou

doi:10.1016/j.jbc.2024.107783

Downregulation of the m⁶A reader YTHDC2 upregulates exosome content in lung adenocarcinoma via inhibiting IFIT and OAS family members

J Biol Chem. 2024 Sep 18:107783. doi: 10.1016/j.jbc.2024.107783. Online ahead of print.

Authors

Zhixin Yin¹, Lifang Ma¹, Xiaoting Tian², Qi Sun², Congcong Zhang³, Yikun Wang¹, Yayou Miao², Xiangfei Xue¹, Yongjie Wang¹, Jiayi Wang⁴, Xiao Zhang⁵, Xumin Hou⁶

Affiliations

¹ Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China.
² Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China.
³ Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
⁴ Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China; Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China. Electronic address: Jiayi.wang@sjtu.edu.cn.
⁵ Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China. Electronic address: 728002276@shsmu.edu.cn.
⁶ Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, 200030, China. Electronic address: hxmchest@163.com.

PMID: 39303913
DOI: 10.1016/j.jbc.2024.107783

Abstract

N⁶-Methyladenosine (m⁶A) is the most prevalent mRNA modification. Its biological function primarily relies on its "Reader" protein, such as YTHDC2. Previous studies have shown that YTHDC2 downregulation is a pro-carcinogenic phenomenon in lung adenocarcinoma (LUAD). However, further investigation is needed to understand the molecular mechanisms of downstream genes and the associated biological phenomena following YTHDC2 downregulation. Here, we found that YTHDC2 knockout upregulated exosome content in LUAD. Following YTHDC2 knockout, the mRNA levels of OAS family members (OASs) and IFIT family members (IFITs) also decreased; and inhibition of OASs and IFITs could promote exosome content. Several m⁶A modification sites on the NT domain of OASs and the TPR12 domain of IFITs were found to increase the stability of OASs and IFITs in a YTHDC2-dependent manner. OASs and IFITs affected exosome content through target genes including RAB5A, RAB7 and RAB11A, and three arginine (R) amino acids on IFITs were critical for combination IFITs with targeted RAB mRNAs and subsequent degradation. Simultaneously, OASs degraded targeted RABs through RNAseL. Additionally, mutual bindings between OASs and IFITs were critical for their target gene degradation. Collectively, the above findings might provide a theoretical basis for the treatment of LUAD patients with low YTHDC2 expression.

Keywords: METTL3; RNA interaction; RNA stability; cancer; immunoprecipitation..