Hypermethylation of DHRS3 as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer.

Sha Sumei,Sha Sumei,Sha Sumei,Nie Yongzhan,Nie Yongzhan,Zhao Qingchuan,Zhao Qingchuan,Hu Sijun,Wu Kaichun,Wu Kaichun,Chen Fenrong,Kong Xiangyun,Kong Xiangyun,Bai Bin,Bai Bin,Tu Yongjiu,Tu Yongjiu,Tu Yongjiu,Shi Xiaolei,Shi Xiaolei,Shi Xiaolei,Sun Xueguang,Xu Bin

doi:10.3389/fcell.2021.624871

Abstract

Background/AimsThe role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.MaterialsBisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.ResultsThe DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.ConclusionDHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.

Highlights

The methylation patterns of DNA are highly variable among cell types and developmental stages and are influenced by environment and lifestyle (Verma and Manne, 2006; Horvath, 2013)
DHRS3 Promoter Was Hypermethylated in Gastric cancer (GC) Patients
Using in silico sequence analysis, we identified a long CpG island with high CpG density in the 5 leader region of DHRS3 gene that spanned the gene promoter and the first exon, implying the potential for epigenetic regulation via DNA methylation

Summary

Introduction

The methylation patterns of DNA are highly variable among cell types and developmental stages and are influenced by environment and lifestyle (Verma and Manne, 2006; Horvath, 2013). It is known that DNA methylation often occurs in gene promoters and is associated with transcriptional silencing of tumor suppressors or other genes important for normal cellular function (Corvalan, 2013; Huang et al, 2015; Gyorffy et al, 2016). These alterations are usually among the earliest and most frequent molecular events known to occur during tumorigenesis (Akhavan-Niaki and Samadani, 2013). It was recently reported that the methylation of some molecules, such as cadherin 4, protocadherin 10, and Runtrelated transcription factor 3 (Satoh et al, 2004; Yu et al, 2009; Llorca-Cardenosa et al, 2016), predisposes patients to GC, suggesting that DNA methylation may play an important role in GC tumorigenesis

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Results

Conclusion