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

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2021 Jun 27

PMID 34174908

Citations 36

Authors

Peixin Dong

Ying Xiong

Yosuke Konno

Kei Ihira

Noriko Kobayashi

Junming Yue

Hidemichi Watari

Affiliations

Soon will be listed here.

Abstract

Background: Epithelial-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.

Methods: We 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.

Results: HK2 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.

Conclusions: This 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.

Citing Articles

Energy metabolism in health and diseases.

Liu H, Wang S, Wang J, Guo X, Song Y, Fu K Signal Transduct Target Ther. 2025; 10(1):69.

PMID: 39966374 PMC: 11836267. DOI: 10.1038/s41392-025-02141-x.

MGAT4A/Galectin9-Driven N-Glycosylation Aberration as a Promoting Mechanism for Poor Prognosis of Endometrial Cancer with TP53 Mutation.

Zhu Z, Sun J, Xu W, Zeng Q, Feng H, Zang L Adv Sci (Weinh). 2024; 11(48):e2409764.

PMID: 39527463 PMC: 11672308. DOI: 10.1002/advs.202409764.

The Promotive and Inhibitory Role of Long Non-Coding RNAs in Endometrial Cancer Course-A Review.

Jasielski P, Zawlik I, Bogaczyk A, Potocka N, Paszek S, Mazniak M Cancers (Basel). 2024; 16(11).

PMID: 38893244 PMC: 11171405. DOI: 10.3390/cancers16112125.

Glucose metabolism reprogramming in gynecologic malignant tumors.

Ma J, Yao Z, Ma L, Zhu Q, Zhang J, Li L J Cancer. 2024; 15(9):2627-2645.

PMID: 38577616 PMC: 10988310. DOI: 10.7150/jca.91131.

LIN28B induced PCAT5 promotes endometrial cancer progression and glycolysis via IGF2BP3 deubiquitination.

Wang B, Wang B, Ma J, He J, Wang Z, Li Q Cell Death Dis. 2024; 15(4):242.

PMID: 38565547 PMC: 10987620. DOI: 10.1038/s41419-024-06564-2.

References

Zhang X, Cai L, Zhou H, Liu Y, Fan C, Wang L . Lasp2 enhances tumor invasion via facilitating phosphorylation of FAK and predicts poor overall survival of non-small cell lung cancer patients. Mol Carcinog. 2017; 56(12):2558-2565. DOI: 10.1002/mc.22700. View

Xu B, Gong X, Zi L, Li G, Dong S, Chen X . Silencing of DLEU2 suppresses pancreatic cancer cell proliferation and invasion by upregulating microRNA-455. Cancer Sci. 2019; 110(5):1676-1685. PMC: 6501038. DOI: 10.1111/cas.13987. View

Cao Q, Mani R, Ateeq B, Dhanasekaran S, Asangani I, Prensner J . Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell. 2011; 20(2):187-99. PMC: 3157014. DOI: 10.1016/j.ccr.2011.06.016. View

Siu M, Jiang Y, Wang J, Leung T, Han C, Tsang B . Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades. Cancers (Basel). 2019; 11(6). PMC: 6627345. DOI: 10.3390/cancers11060813. View

Wang S, Zuo H, Jin J, Lv W, Xu Z, Fan Y . Long noncoding RNA Neat1 modulates myogenesis by recruiting Ezh2. Cell Death Dis. 2019; 10(7):505. PMC: 6594961. DOI: 10.1038/s41419-019-1742-7. View

Njoku K, Chiasserini D, Whetton A, Crosbie E . Proteomic Biomarkers for the Detection of Endometrial Cancer. Cancers (Basel). 2019; 11(10). PMC: 6826703. DOI: 10.3390/cancers11101572. View

Brabletz T, Kalluri R, Nieto M, Weinberg R . EMT in cancer. Nat Rev Cancer. 2018; 18(2):128-134. DOI: 10.1038/nrc.2017.118. View

Ling Z, Wang X, Tao T, Zhang L, Guan H, You Z . Involvement of aberrantly activated HOTAIR/EZH2/miR-193a feedback loop in progression of prostate cancer. J Exp Clin Cancer Res. 2017; 36(1):159. PMC: 5688662. DOI: 10.1186/s13046-017-0629-7. View

Tsai C, Wu H, Lin C, Lin Y, Chao A, Wang T . Estradiol and tamoxifen induce cell migration through GPR30 and activation of focal adhesion kinase (FAK) in endometrial cancers with low or without nuclear estrogen receptor α (ERα). PLoS One. 2013; 8(9):e72999. PMC: 3767783. DOI: 10.1371/journal.pone.0072999. View

10.

Ihira K, Dong P, Xiong Y, Watari H, Konno Y, Hanley S . EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. Oncotarget. 2017; 8(8):13509-13520. PMC: 5355116. DOI: 10.18632/oncotarget.14586. View

11.

Thang N, Yajima I, Kumasaka M, Iida M, Suzuki T, Kato M . Deltex-3-like (DTX3L) stimulates metastasis of melanoma through FAK/PI3K/AKT but not MEK/ERK pathway. Oncotarget. 2015; 6(16):14290-9. PMC: 4546467. DOI: 10.18632/oncotarget.3742. View

12.

Chen G, Zhang Y, Liang J, Li W, Zhu Y, Zhang M . Deregulation of Hexokinase II Is Associated with Glycolysis, Autophagy, and the Epithelial-Mesenchymal Transition in Tongue Squamous Cell Carcinoma under Hypoxia. Biomed Res Int. 2018; 2018:8480762. PMC: 5841093. DOI: 10.1155/2018/8480762. View

13.

Xu D, Dong P, Xiong Y, Yue J, Konno Y, Ihira K . MicroRNA-361-Mediated Inhibition of HSP90 Expression and EMT in Cervical Cancer Is Counteracted by Oncogenic lncRNA NEAT1. Cells. 2020; 9(3). PMC: 7140536. DOI: 10.3390/cells9030632. View

14.

Zhao Y, Yan M, Yun Y, Zhang J, Zhang R, Li Y . MicroRNA-455-3p functions as a tumor suppressor by targeting eIF4E in prostate cancer. Oncol Rep. 2017; 37(4):2449-2458. DOI: 10.3892/or.2017.5502. View

15.

Guo Y, Bai M, Lin L, Huang J, An Y, Liang L . LncRNA DLEU2 aggravates the progression of hepatocellular carcinoma through binding to EZH2. Biomed Pharmacother. 2019; 118:109272. DOI: 10.1016/j.biopha.2019.109272. View

16.

Yu J, Jiang L, Gao Y, Sun Q, Liu B, Hu Y . LncRNA CCAT1 negatively regulates miR-181a-5p to promote endometrial carcinoma cell proliferation and migration. Exp Ther Med. 2019; 17(5):4259-4266. PMC: 6447908. DOI: 10.3892/etm.2019.7422. View

17.

Yu J, Li J, Chen Y, Cao W, Lu Y, Yang J . Snail Enhances Glycolysis in the Epithelial-Mesenchymal Transition Process by Targeting FBP1 in Gastric Cancer. Cell Physiol Biochem. 2017; 43(1):31-38. DOI: 10.1159/000480314. View

18.

Jia N, Li Q, Tao X, Wang J, Hua K, Feng W . Enhancer of zeste homolog 2 is involved in the proliferation of endometrial carcinoma. Oncol Lett. 2014; 8(5):2049-2054. PMC: 4186594. DOI: 10.3892/ol.2014.2437. View

19.

Sun Y, Wang Y, Yang H, Xu Y, Yu H . miR-455-3p functions as a tumor suppressor in colorectal cancer and inhibits cell proliferation by targeting TPT1. Int J Clin Exp Pathol. 2020; 11(5):2522-2529. PMC: 6958251. View

20.

Brooks R, Fleming G, Lastra R, Lee N, Moroney J, Son C . Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin. 2019; 69(4):258-279. DOI: 10.3322/caac.21561. View