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

Journal of Experimental & Clinical Cancer Research

Ying Xiong¹  Kei Ihira²  Noriko Kobayashi²  Peixin Dong²  Yosuke Konno²  Hidemichi Watari²  Junming Yue³ 

[1] Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China;Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Hokkaido University, 0608638, Sapporo, Japan;Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, 38163, Memphis, TN, USA;Center for Cancer Research, University of Tennessee Health Science Center, 38163, Memphis, TN, USA;

关键词: HK2;    FAK;    ERK1/2 signaling;    DLEU2;    Long noncoding RNA;    LncRNA;    MicroRNA;    EMT;    Aerobic glycolysis;    Endometrial cancer;   

DOI  :  10.1186/s13046-021-02018-1

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY