Ginsenoside Rg3 Prevents Oncogenic Long Noncoding RNA ATXN8OS from Inhibiting Tumor-Suppressive microRNA-424-5p in Breast Cancer Cells.

Heejoo Kim,Jae Eun Park,Hyeon Woo Kim,Hwee Won Ji,Sung Hwan Yun,Sun Jung Kim

doi:10.3390/biom11010118

Abstract

Ginsenoside Rg3 exerts antiproliferation activity on cancer cells by regulating diverse noncoding RNAs. However, little is known about the role of long noncoding RNAs (lncRNAs) or their relationship with competitive endogenous RNA (ceRNA) in Rg3-treated cancer cells. Here, a lncRNA (ATXN8OS) was found to be downregulated via Rg3-mediated promoter hypermethylation in MCF-7 breast cancer cells. SiRNA-induced downregulation of ATXN8OS decreased cell proliferation but increased apoptosis, suggesting that the noncoding RNA possessed proproliferation activity. An in silico search for potential ATXN8OS-targeting microRNAs (miRs) identified a promising candidate (miR-424-5p) based on its high binding score. As expected, miR-424-5p suppressed proliferation and stimulated apoptosis of the MCF-7 cells. The in silico miR-target-gene prediction identified 200 potential target genes of miR-424-5p, which were subsequently narrowed down to seven that underwent hypermethylation at their promoter by Rg3. Among them, three genes (EYA1, DACH1, and CHRM3) were previously known oncogenes and were proven to be oppositely regulated by ATXN8OS and miR-424-5p. When taken together, Rg3 downregulated ATXN8OS that inhibited the tumor-suppressive miR-424-5p, leading to the downregulation of the oncogenic target genes.

Highlights

IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Given that many long noncoding RNAs (lncRNAs) have been linked to the development of various cancer types, our study focused on their regulatory mechanisms
Our study aimed to identify lncRNAs that are dysregulated in Rg3-treated cancer cells to elucidate the mechanisms by which they control cancer-cell proliferation, with a particular focus on competitive endogenous RNA (ceRNA)-miR interaction

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Ginsenoside Rg3 is a steroidal saponin derivative that is abundant in heat-processed ginseng extract [1]. Rg3 possesses potent anticancer properties and is known to modulate diverse cellular events such as cell proliferation, immune response, autophagy, metastasis, and angiogenesis [2]. Rg3 activates proapoptotic proteins such as caspase-3 and Bax but suppresses antiapoptotic protein Bcl-2 [3]. NF-κB, which drives cell-cycle progression, is inhibited by blocking the phosphorylation of Akt and ERK kinases [4]

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