DNMT3A-mediated silence in ADAMTS9 expression is restored by RNF180 to inhibit viability and motility in gastric cancer cells

Weilin Sun,Nannan Zhang,Liqiao Chen,Huifang Liu,Fenglin Cai,Li Zhang,Han Liang,Pengliang Wang,Yinping Dong,Gang Ma,Zizhen Wu,Jingyu Deng

doi:10.1038/s41419-021-03628-5

Abstract

ADAMTS9 belongs to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family, and its expression is frequently silenced due to promoter hypermethylation in various human cancers. However, the underlying mechanisms remain largely unknown. In this study, we investigated the inhibitory effects of ADAMTS9 on gastric cancer (GC) cells. We initially examined ADAMTS9 protein level in 135 GC and adjacent normal tissue pairs, showing that ADAMTS9 was strikingly decreased in the malignant specimens and patients with low ADAMTS9 expression exhibited more malignant phenotypes and poorer outcome. ADAMTS9 expression was restored in AGS and BGC-823 cells, which then markedly suppressed cellular viability and motility in vitro and in vivo. As ADAMTS9 was enriched in the nuclei of gastric mucosal cells, RNA-sequencing experiment showed that ADAMTS9 significantly altered gene expression profile in BGC-823 cells. Additionally, DNA methyltransferase 3α (DNMT3A) was identified to be responsible for the hypermethylation of ADAMTS9 promoter, and this methyltransferase was ubiquitinated by ring finger protein 180 (RNF180) and then subject to proteasome-mediated degradation. In conclusion, we uncovered RNF180/DNMT3A/ADAMTS9 axis in GC cells and showed how the signaling pathway affected GC cells.

Highlights

Introduction Aberrant promoterDNA hypermethylation is a welldefined epigenetic hallmark in all human tumor types
Our study demonstrated that ADAMTS9 inhibited the viability, migration, and invasion of gastric cancer (GC) cells
Our findings suggested that ADAMTS9 might be a potential biomarker for predicting the prognosis of GC patients and help improve our understanding of the mechanism of GC development

Summary

Introduction

Introduction Aberrant promoterDNA hypermethylation is a welldefined epigenetic hallmark in all human tumor types. We investigated the inhibitory functions of ADAMTS9 in GC, showing that ADAMTS9 expression was decreased in malignant tissues and this low level was positively associated with advanced stage and poor overall survival (OS) in patients with GC. As ADAMTS9 was partially localized in the nuclei, we performed RNA-sequencing assay and showed that this protein altered the expressions of dozens of genes in BGC823 cells, some of which are closely related with viability and motility in GC cells.

Results

Conclusion