PMID- 34326314
OWN - NLM
STAT- MEDLINE
DCOM- 20220127
LR  - 20220127
IS  - 2041-4889 (Electronic)
VI  - 12
IP  - 8
DP  - 2021 Jul 29
TI  - EGR2-mediated regulation of m(6)A reader IGF2BP proteins drive RCC tumorigenesis 
      and metastasis via enhancing S1PR3 mRNA stabilization.
PG  - 750
LID - 10.1038/s41419-021-04038-3 [doi]
LID - 750
AB  - Emerging discoveries of dynamic and reversible N6-methyladenosine (m(6)A) 
      modification on RNA in mammals have revealed the key roles of the modification in 
      human tumorigenesis. As known m(6)A readers, insulin-like growth factor 2 
      mRNA-binding proteins (IGF2BPs) are upregulated in most cancers and mediates the 
      enhancement of m(6)A-modified mRNAs stability. However, the mechanisms of IGF2BPs 
      in renal cell cancer (RCC) still remain unclear. Bioinformatic analysis and 
      RT-qPCR were performed to evaluate the expression of IGF2BPs and m(6)A writer 
      Wilms tumor 1-associating protein (WTAP) in RCC samples and its correlation with 
      patient prognosis. In vitro, in vivo biological assays were performed to 
      investigate the functions of IGF2BPs and WTAP in RCC. Chromatin 
      immunoprecipitation-qPCR (ChIP-qPCR) combined with bioinformatics analysis and 
      following western blot assay, dual-luciferase reporter assays were performed to 
      validate the regulatory relationships between transcription factor (TF) early 
      growth response 2 (EGR2) and potential target genes IGF2BPs. RNA sequencing 
      (RNA-seq), methylated RNA immunoprecipitation-qPCR (MERIP-qPCR), RIP-qPCR, m(6)A 
      dot blot, and dual-luciferase reporter assays combined with bioinformatics 
      analysis were employed to screen and validate the direct targets of IGF2BPs and 
      WTAP. Here, we showed that early growth response 2 (EGR2) transcription factor 
      could increase IGF2BPs expression in RCC. IGF2BPs in turn regulated 
      sphingosine-1-phosphate receptor 3 (S1PR3) expression in an m(6)A-dependent 
      manner by enhancing the stability of S1PR3 mRNA. They also promoted kidney 
      tumorigenesis via PI3K/AKT pathway. Furthermore, IGF2BPs and WTAP upregulation 
      predicted poor overall survival in RCC. Our studies showed that the EGR2/IGF2BPs 
      regulatory axis and m(6)A-dependent regulation of S1PR3-driven RCC tumorigenesis, 
      which enrich the m(6)A-modulated regulatory network in renal cell cancer. 
      Together, our findings provide new evidence for the role of N6-methyladenosine 
      modification in RCC.
CI  - (c) 2021. The Author(s).
FAU - Ying, Yufan
AU  - Ying Y
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Ma, Xueyou
AU  - Ma X
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Fang, Jiajie
AU  - Fang J
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Chen, Shiming
AU  - Chen S
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Wang, Weiyu
AU  - Wang W
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Li, Jiangfeng
AU  - Li J
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Xie, Haiyun
AU  - Xie H
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Wu, Jian
AU  - Wu J
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Xie, Bo
AU  - Xie B
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
FAU - Liu, Ben
AU  - Liu B
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China.
AD  - Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
FAU - Wang, Xiao
AU  - Wang X
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China. zjuwangxiao@zju.edu.cn.
FAU - Zheng, Xiangyi
AU  - Zheng X
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China. zheng_xy@zju.edu.cn.
AD  - Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China. 
      zheng_xy@zju.edu.cn.
FAU - Xie, Liping
AU  - Xie L
AD  - Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang 
      University, 310000, Hangzhou, Zhejiang, China. xielp@zju.edu.cn.
AD  - Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China. 
      xielp@zju.edu.cn.
LA  - eng
GR  - 2020M681885/China Postdoctoral Science Foundation/
GR  - LQ21H160030/Natural Science Foundation of Zhejiang Province (Zhejiang Provincial 
      Natural Science Foundation)/
GR  - LY20H160022/Natural Science Foundation of Zhejiang Province (Zhejiang Provincial 
      Natural Science Foundation)/
GR  - 81874203/National Natural Science Foundation of China (National Science 
      Foundation of China)/
GR  - 81802564/National Natural Science Foundation of China (National Science 
      Foundation of China)/
GR  - 81972374/National Natural Science Foundation of China (National Science 
      Foundation of China)/
GR  - 82072848/National Natural Science Foundation of China (National Science 
      Foundation of China)/
GR  - 81772744/National Natural Science Foundation of China (National Science 
      Foundation of China)/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210729
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EGR2 protein, human)
RN  - 0 (Early Growth Response Protein 2)
RN  - 0 (IGF2BP1 protein, human)
RN  - 0 (RNA Splicing Factors)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Sphingosine-1-Phosphate Receptors)
RN  - 0 (WTAP protein, human)
RN  - 0 (sphingosine-1-phosphate receptor-3, human)
RN  - CLE6G00625 (N-methyladenosine)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/*analogs & derivatives/metabolism
MH  - Adult
MH  - Aged
MH  - Carcinogenesis/*drug effects
MH  - Carcinoma, Renal Cell/*genetics
MH  - Cell Cycle Proteins/metabolism
MH  - Cell Line, Tumor
MH  - Cell Movement/genetics
MH  - Cell Proliferation/genetics
MH  - Early Growth Response Protein 2/*metabolism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Kidney Neoplasms/*genetics
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Metastasis
MH  - Prognosis
MH  - RNA Splicing Factors/metabolism
MH  - RNA Stability/*genetics
MH  - RNA, Messenger
MH  - RNA-Binding Proteins/genetics/*metabolism
MH  - Sphingosine-1-Phosphate Receptors/*genetics/metabolism
MH  - Survival Analysis
MH  - Transcription, Genetic
PMC - PMC8322060
COIS- The authors declare no competing interests.
EDAT- 2021/07/31 06:00
MHDA- 2022/01/28 06:00
PMCR- 2021/07/29
CRDT- 2021/07/30 05:53
PHST- 2021/04/14 00:00 [received]
PHST- 2021/07/19 00:00 [accepted]
PHST- 2021/07/16 00:00 [revised]
PHST- 2021/07/30 05:53 [entrez]
PHST- 2021/07/31 06:00 [pubmed]
PHST- 2022/01/28 06:00 [medline]
PHST- 2021/07/29 00:00 [pmc-release]
AID - 10.1038/s41419-021-04038-3 [pii]
AID - 4038 [pii]
AID - 10.1038/s41419-021-04038-3 [doi]
PST - epublish
SO  - Cell Death Dis. 2021 Jul 29;12(8):750. doi: 10.1038/s41419-021-04038-3.