Snail/PRMT5/NuRD complex contributes to DNA hypermethylation in cervical cancer by TET1 inhibition

Jie Gao,Ruiqiong Liu,Yang Yang,Dandan Feng,Wei Huang,Tianshu Yang,Miaomiao Huo,Shuai Leng,Yan Wang,Jingyao Zhang,Baowen Yuan,Xu Teng,Hefen Yu,Xin Yin

doi:10.1038/s41418-021-00786-z

Abstract

The biological function of PRMT5 remains poorly understood in cervical cancer metastasis. Here, we report that PRMT5 physically associates with the transcription factor Snail and the NuRD(MTA1) complex to form a transcriptional-repressive complex that catalyzes the symmetrical histone dimethylation and deacetylation. This study shows that the Snail/PRMT5/NuRD(MTA1) complex targets genes, such as TET1 and E-cadherin, which are critical for epithelial-mesenchymal transition (EMT). This complex also affects the conversion of 5mC to 5hmC. This study demonstrates that the Snail/PRMT5/NuRD(MTA1) complex promotes the invasion and metastasis of cervical cancer in vitro and in vivo. This study also shows that PRMT5 expression is upregulated in cervical cancer and various human cancers, and the PRMT5 inhibitor EPZ015666 suppresses EMT and the invasion potential of cervical cancer cells by disinhibiting the expression of TET1 and increasing 5hmC, suggesting that PRMT5 is a potential target for cancer therapy.

Highlights

These authors contributed : Jie Gao, Ruiqiong Liu, Dandan FengEdited by R Johnstone
Our results revealed that Protein arginine methyltransferase 5 (PRMT5) enables Snail and the NuRD(MTA1) complex to perform transcriptional silencing of a cohort of target genes, such as TET1, FOXK2, E
The study identified PRMT5 as a repressor recruited to the Snail complex via interaction with the AJUBA corepressor, but it is not clear whether there is a direct interaction between PRMT5 and Snail

Summary

1234567890();,: 1234567890();,: Introduction

The zinc finger motifs of Snail can recognize the E-box sequence of target genes and the SNAG domain can recruit a variety of repressive cofactors. Snail can recruit the polycomb repressive complex 2 (PRC2), G9A, SUV39H1, corepressor SIN3A, HDAC1, 2 and 3, and LSD1, which coordinate histone modifications such as methylation and acetylation of H3K4, H3K9, and H3K27 [22–25]. These studies demonstrated that Snail plays an important role in tumor metastasis and recurrence. We found that PRMT5 coordinates with Snail and the NuRD(MTA1) complex to achieve transcriptional silencing of target genes including TET1, Ecadherin, and others. Our data suggest that the PRMT5 inhibitor EPZ015666 can lead to an induction of TET1 expression and 5hmC, and inhibit the invasive potential of cervical cancer cells, making PRMT5 a potential target for cancer diagnosis and treatment

Materials and methods

Results

Discussion

Compliance with ethical standards