CPEB2 m6A methylation regulates blood-tumor barrier permeability by regulating splicing factor SRSF5 stability

Mengyang Zhang; Chunqing Yang; Xuelei Ruan; Xiaobai Liu; Di Wang; Libo Liu; Lianqi Shao; Ping Wang; Weiwei Dong; Yixue Xue

doi:10.1038/s42003-022-03878-9

CPEB2 m6A methylation regulates blood-tumor barrier permeability by regulating splicing factor SRSF5 stability

Commun Biol. 2022 Sep 5;5(1):908. doi: 10.1038/s42003-022-03878-9.

Authors

Mengyang Zhang^{1

2

3}, Chunqing Yang^{4

5

6}, Xuelei Ruan^{1

2

3}, Xiaobai Liu^{4

5

6}, Di Wang^{4

5

6}, Libo Liu^{1

2

3}, Lianqi Shao^{1

2

3}, Ping Wang^{1

2

3}, Weiwei Dong^{4

5

6}, Yixue Xue^{7

8

9}

Affiliations

¹ Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, PR China.
² Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, PR China.
³ Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, PR China.
⁴ Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, PR China.
⁵ Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang, PR China.
⁶ Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, PR China.
⁷ Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, PR China. xueyixue88cmu@163.com.
⁸ Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, PR China. xueyixue88cmu@163.com.
⁹ Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, PR China. xueyixue88cmu@163.com.

Abstract

The blood-tumor barrier (BTB) contributes to poor therapeutic efficacy by limiting drug uptake; therefore, elevating BTB permeability is essential for glioma treatment. Here, we prepared astrocyte microvascular endothelial cells (ECs) and glioma microvascular ECs (GECs) as in vitro blood-brain barrier (BBB) and BTB models. Upregulation of METTL3 and IGF2BP3 in GECs increased the stability of CPEB2 mRNA through its m6A methylation. CPEB2 bound to and increased SRSF5 mRNA stability, which promoted the ETS1 exon inclusion. P51-ETS1 promoted the expression of ZO-1, occludin, and claudin-5 transcriptionally, thus regulating BTB permeability. Subsequent in vivo knockdown of these molecules in glioblastoma xenograft mice elevated BTB permeability, promoted doxorubicin penetration, and improved glioma-specific chemotherapeutic effects. These results provide a theoretical and experimental basis for epigenetic regulation of the BTB, as well as insight into comprehensive glioma treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / metabolism
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
Endothelial Cells / metabolism
Epigenesis, Genetic
Glioma* / drug therapy
Glioma* / genetics
Glioma* / metabolism
Humans
Methylation
Methyltransferases* / genetics
Methyltransferases* / metabolism
Mice
MicroRNAs / genetics
MicroRNAs / metabolism
Microvessels / metabolism
Permeability
RNA Splicing Factors / genetics
RNA Splicing Factors / metabolism
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Serine-Arginine Splicing Factors* / genetics
Serine-Arginine Splicing Factors* / metabolism
Zonula Occludens-1 Protein / genetics
Zonula Occludens-1 Protein / metabolism

Substances

CPEB2 protein, human
CPEB2 protein, mouse
MicroRNAs
RNA Splicing Factors
RNA-Binding Proteins
SRSF5 protein, human
SRSF5 protein, mouse
Zonula Occludens-1 Protein
Serine-Arginine Splicing Factors
Methyltransferases
Mettl3 protein, mouse
METTL3 protein, human