EGR2-mediated regulation of m6A reader IGF2BP proteins drive RCC tumorigenesis and metastasis via enhancing S1PR3 mRNA stabilization

• DOI: 10.1038/s41419-021-04038-3
• Publication Date: 2021-07-29T06:02:57Z
• Authors: Yufan Ying; Xueyou Ma; Jiajie Fang; Shiming Chen; Weiyu Wang; Jiangfeng Li; Haiyun Xie; Jian Wu; Bo Xie; Ben Liu; Xiao Wang; Xiangyi Zheng; Liping Xie
• Keywords: Adult; Male; 0301 basic medicine; Adenosine; Carcinogenesis; RNA Stability; Cell Cycle Proteins; Article; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Humans; Neoplasm Metastasis; Carcinoma, Renal Cell; Early Growth Response Protein 2; Aged; Cell Proliferation; QH573-671; Middle Aged; Prognosis; Kidney Neoplasms; 3. Good health; Gene Expression Regulation, Neoplastic; Female; RNA Splicing Factors; Cytology

Emerging discoveries of dynamic and reversible N6-methyladenosine (m6A) modification on RNA in mammals have revealed the key roles human tumorigenesis. As known m6A readers, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are upregulated most cancers mediates enhancement m6A-modified mRNAs stability. However, mechanisms IGF2BPs renal cell cancer (RCC) still remain unclear. Bioinformatic analysis RT-qPCR were performed to evaluate expression writer Wilms tumor 1-associating protein (WTAP) RCC samples its correlation with patient prognosis. In vitro, vivo biological assays investigate functions WTAP RCC. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) combined bioinformatics following western blot assay, dual-luciferase reporter validate regulatory relationships between transcription (TF) early response (EGR2) potential target genes IGF2BPs. sequencing (RNA-seq), methylated (MERIP-qPCR), RIP-qPCR, dot blot, employed screen direct targets WTAP. Here, we showed that could increase turn regulated sphingosine-1-phosphate receptor 3 (S1PR3) an m6A-dependent manner by enhancing stability S1PR3 mRNA. They also promoted kidney tumorigenesis via PI3K/AKT pathway. Furthermore, upregulation predicted poor overall survival Our studies EGR2/IGF2BPs axis regulation S1PR3-driven tumorigenesis, which enrich m6A-modulated network cancer. Together, our findings provide new evidence for role