Long non-coding RNA DLEU2 drives EMT and glycolysis in endometrial cancer through HK2 by competitively binding with miR-455 and by modulating the EZH2/miR-181a pathway

Peixin Dong,Junming Yue,Yosuke Konno,Hidemichi Watari,Noriko Kobayashi,Kei Ihira,Ying Xiong

doi:10.1186/s13046-021-02018-1

Abstract

BackgroundEpithelial-to-mesenchymal transition (EMT) and aerobic glycolysis are fundamental processes implicated in cancer metastasis. Although increasing evidence demonstrates an association between EMT induction and enhanced aerobic glycolysis in human cancer, the mechanisms linking these two conditions in endometrial cancer (EC) cells remain poorly defined.MethodsWe characterized the role and molecular mechanism of the glycolytic enzyme hexokinase 2 (HK2) in mediating EMT and glycolysis and investigated how long noncoding RNA DLEU2 contributes to the stimulation of EMT and glycolysis via upregulation of HK2 expression.ResultsHK2 was highly expressed in EC tissues, and its expression was associated with poor overall survival. Overexpression of HK2 effectively promoted EMT phenotypes and enhanced aerobic glycolysis in EC cells via activating FAK and its downstream ERK1/2 signaling. Moreover, microRNA-455 (miR-455) served as a tumor suppressor by directly interacting with HK2 mRNA and inhibiting its expression. Furthermore, DLEU2 displayed a significantly higher expression in EC tissues, and increased DLEU2 expression was correlated with worse overall survival. DLEU2 acted as an upstream activator for HK2-induced EMT and glycolysis in EC cells through two distinct mechanisms: (i) DLEU2 induced HK2 expression by competitively binding with miR-455, and (ii) DLEU2 also interacted with EZH2 to silence a direct inhibitor of HK2, miR-181a.ConclusionsThis study identified DLEU2 as an upstream activator of HK2-driven EMT and glycolysis in EC cells and provided significant mechanistic insights for the potential treatment of EC.

Highlights

Epithelial-to-mesenchymal transition (EMT) and aerobic glycolysis are fundamental processes implicated in cancer metastasis
Hexokinase 2 (HK2) is overexpressed in endometrial cancer (EC) and predicts a worse prognosis The analysis of public datasets from The Cancer Genome Atlas (TCGA) via the cBioPortal database showed that HK2 was frequently amplified in various human cancers, including EC (Fig. 1a)
According to Oncomine, we found a significant increase in the DNA copy number of HK2 gene in different subtypes of EC tissues compared with normal tissues (Fig. 1c)

Summary

Introduction

Epithelial-to-mesenchymal transition (EMT) and aerobic glycolysis are fundamental processes implicated in cancer metastasis. Increasing evidence demonstrates an association between EMT induction and enhanced aerobic glycolysis in human cancer, the mechanisms linking these two conditions in endometrial cancer (EC) cells remain poorly defined. There is increasing evidence demonstrating an association between EMT execution and the reprogramming of glucose metabolism [8]. Snail serves as a positive regulator of EMT and glucose metabolism in gastric cancer [9], and HK2 was reported to increase glycolytic activity and ovarian cancer cell invasiveness through upregulation of the EMT activator, focal adhesion kinase (FAK) [10, 11], indicating that the overlapping mechanisms exist to affect both EMT and aerobic glycolysis

Methods

Results

Discussion

Conclusion