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

被引：0

作者：

Yin, Zhixin ^{[1
,2
]}

Ma, Lifang ^{[1
,2
]}

Tian, Xiaoting ^{[2
]}

Sun, Qi ^{[2
]}

Zhang, Congcong ^{[1
]}

Wang, Yikun ^{[1
,2
]}

Miao, Yayou ^{[2
]}

Xue, Xiangfei ^{[1
,2
]}

Wang, Yongjie ^{[1
,2
]}

Wang, Jiayi ^{[1
,2
]}

Zhang, Xiao ^{[2
]}

Hou, Xumin ^{[3
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Sch Med, Dept Clin Lab Med, Shanghai, Peoples R China

[2] Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Shanghai Inst Thorac Oncol, Sch Med, Shanghai, Peoples R China

[3] Shanghai Jiao Tong Univ, Sch Med, Shanghai Chest Hosp, Dept Cardiol, Shanghai, Peoples R China

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2024年 / 300卷 / 10期

关键词：

CANCER-CELLS; BINDING; RECOGNITION; TRANSLATION; PROGRESSION; ACTIVATION; RESISTANCE; THERAPIES; PROMOTES; PROTEIN;

D O I：

10.1016/j.jbc.2024.107783

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

N6-Methyladenosine 6-Methyladenosine (m6A) 6 A) is the most prevalent mRNA modification. fi cation. Its biological function primarily relies on its "Reader" protein, such as YTHDC2. Previous studies have shown that YTHDC2 downregulation is a procarcinogenic 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 6 A modification fi cation 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 YTHDC2dependent 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 fi ndings might provide a theoretical basis for the treatment of LUAD patients with low YTHDC2 expression.

引用

页数：18