Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism
Dong, J.1,2; Xiao, D.2; Zhao, Z.3; Ren, P.4; Li, C.5; Hu, Y.2; Shi, J.6; Su, H.2,6; Wang, L.2; Liu, H.2; Li, B.5; Gao, P.7,8; Qing, G.1,2
Source PublicationONCOGENESIS
Indexed BySCI
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectOncology
WOS Research AreaOncology
AbstractTumor cells must activate specific transporters to meet their increased glutamine metabolic demands. Relative to other glutamine transporters, the ASC family transporter 2 (ASCT2, also called SLC1A5) is profoundly elevated in a wide spectrum of human cancers to coordinate metabolic reprogramming and malignant transformation. Understanding the molecular mechanisms whereby tumor cells frequently upregulate this transporter is therefore vital to develop potential strategies for transporter-targeted therapies. Combining in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor microRNA, miR-137, as an essential regulator that targets ASCT2 and cancer cell glutamine metabolism. Metabolic analysis shows that miR-137 derepression, similar to ASCT2 inactivation, significantly inhibits glutamine consumption and TCA cycle anaplerosis. Mechanistically, methyl-CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote active methylation of the miR-137 promoter and inhibit its transcription, conversely reactivating ASCT2 expression and glutamine metabolism. Moreover, expression between miR-137 and ASCT2 is inversely correlated in tumor specimens from multiple cancer types, and ectopic ASCT2 expression markedly rescued miR-137 suppression of tumorigenesis. These findings thus elucidate a previously unreported mechanism responsible for ASCT2 deregulation in human cancers and identify ASCT2 as a critical downstream effector of miR-137, revealing a molecular link between DNA methylation, microRNA and tumor metabolism.
WOS IDWOS:000408140600008
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Cited Times:12[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Affiliation1.Huazhong Univ Sci & Technol, Sch Basic Med, Dept Pharmacol, Tongji Med Coll, Wuhan, Hubei, Peoples R China
2.Wuhan Univ, Med Res Inst, Dept Canc Biol, 185 East Lake Rd, Wuhan 430071, Hubei, Peoples R China
3.Dalian Med Univ, Clin Lab, Hosp 2, Dalian, Peoples R China
4.Hubei Univ Sci & Technol, Sch Pharm, Xianning, Peoples R China
5.Sun Yat Sen Univ, Zhongshan Sch Med, Dept Biochem & Mol Biol, Guangzhou, Guangdong, Peoples R China
6.Huazhong Univ Sicence & Technol, Union Hosp, Tongji Med Coll, Wuhan, Hubei, Peoples R China
7.Dalian Med Univ, Affiliated Dalian Peoples Hosp 6, Dalian, Peoples R China
8.Dalian Inst Chem Phys, Dept Biotechnol, Dalian, Peoples R China
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GB/T 7714
Dong, J.,Xiao, D.,Zhao, Z.,et al. Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism[J]. ONCOGENESIS,2017,6.
APA Dong, J..,Xiao, D..,Zhao, Z..,Ren, P..,Li, C..,...&Qing, G..(2017).Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism.ONCOGENESIS,6.
MLA Dong, J.,et al."Epigenetic silencing of microRNA-137 enhances ASCT2 expression and tumor glutamine metabolism".ONCOGENESIS 6(2017).
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