SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs

Author:

Hou Guofang12,Zhao Xian1,Li Lian1,Yang Qianqian1,Liu Xiaojia1,Huang Caihu1,Lu Runhui1,Chen Ran1,Wang Yanli1,Jiang Bin2,Yu Jianxiu1ORCID

Affiliation:

1. State Key Laboratory of Oncogenes and Related Genes, Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

2. Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 280 Mohe Road, Shanghai 201999, China

Abstract

Abstract N 6-Methyladenosine (m6A) is the most abundant modification within diverse RNAs including mRNAs and lncRNAs and is regulated by a reversible process with important biological functions. Human YTH domain family 2 (YTHDF2) selectively recognized m6A-RNAs to regulate degradation. However, the possible regulation of YTHDF2 by protein post-translational modification remains unknown. Here, we show that YTHDF2 is SUMOylated in vivo and in vitro at the major site of K571, which can be induced by hypoxia while reduced by oxidative stress and SUMOylation inhibitors. SUMOylation of YTHDF2 has little impact on its ubiquitination and localization, but significantly increases its binding affinity of m6A-modified mRNAs and subsequently results in deregulated gene expressions which accounts for cancer progression. Moreover, Disease-free survival analysis of patients with lung adenocarcinoma derived from TCGA dataset reveals that higher expression of YTHDF2 together with higher expression of SUMO1 predicts poor prognosis. Our works uncover a new regulatory mechanism for YTHDF2 recognition of m6A-RNAs and highlight the importance of YTHDF2 SUMOylation in post-transcriptional gene expression regulation and cancer progression.

Funder

National Natural Science Foundation of China

National Key Research and Development Program

Publisher

Oxford University Press (OUP)

Subject

Genetics

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