LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2
LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2
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LncRNA EPB41L4A-AS1 通过介导 HDAC2 核仁易位调节糖酵解和谷氨酰胺分解
DOI：
10.1016/j.ebiom.2019.01.035
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发表时间：
2019-03-01
期刊：
影响因子：
11.1
通讯作者：
Zhang, Yaou
中科院分区：
文献类型：
--
作者：
Liao, Meijian;Liao, Weijie;Zhang, Yaou
背景：lncrna已被发现参与生物过程的各个方面。在本研究中，我们旨在揭示lncRNA EPB41L4A-AS1调控癌细胞糖酵解和谷氨酰胺解的分子机制。方法：采用TCGA和GEO数据集分析肿瘤患者EPB41L4A-AS1的表达情况。细胞外通量分析仪测定细胞代谢水平。采用qRT-PCR、荧光素酶法和ChIP法探讨p53与EPB41L4A-AS1的关系。采用RNA免疫沉淀法、RNA下拉法和RNA- fish免疫荧光法检测EPB41L4A-AS1与HDAC2或NPM1的相互作用。结果：EPB41L4A-AS1是p53调控基因。lncRNA EPB41L4A-AS1的低表达和缺失存在于多种人类癌症中，并与癌症患者预后不良相关。敲低EPB41L4A-AS1表达可触发Warburg效应，表现为有氧糖酵解和谷氨酰胺酵解增加。EPB41L4A-AS1在核仁中与HDAC2和NPM1相互作用和共定位。EPB41L4A-AS1的沉默降低了HDAC2与NPM1的相互作用，使HDAC2从核仁释放并增加其在核质中的分布，增强了HDAC2在VHL和VDAC1启动子区域的占据，最终加速糖酵解和谷氨酰胺水解。在肿瘤治疗中，EPB41L4A-AS1的缺失增加了肿瘤对谷氨酰胺酶抑制剂的敏感性。解释：EPB41L4A-AS1作为Warburg效应的抑制因子，在癌症代谢重编程中发挥重要作用。(c) 2019年Elsevier B.V.出版
Background: LncRNAs have been found to be involved in various aspects of biological processes. In this study, we aimed to uncover the molecular mechanisms of lncRNA EPB41L4A-AS1 in regulating glycolysis and glutaminolysis in cancer cells.Methods: The expression of EPB41L4A-AS1 in cancer patients was analyzed in TCGA and GEO datasets. The level of cellular metabolism was determined by extracellular flux analyzer. The relationship between p53 and EPB41L4A-AS1 was explored by qRT-PCR, luciferase assay and ChIP assay. The interactions between EPB41L4A-AS1 and HDAC2 or NPM1 were determined by RNA immunoprecipitation, RNA pull-down assay and RNA-FISH-immunofluorescence.Findings: EPB41L4A-AS1 was a p53-regulated gene. Low expression and deletion of lncRNA EPB41L4A-AS1 were found in a variety of human cancers and associated with poor prognosis of cancer patients. Knock down EPB41L4A-AS1 expression triggered Warburg effect, demonstrated as increased aerobic glycolysis and glutaminolysis. EPB41L4A-AS1 interacted and colocalized with HDAC2 and NPM1 in nucleolus. Silencing EPB41L4A-AS1 reduced the interaction between HDAC2 and NPM1, released HDAC2 from nucleolus and increased its distribution in nucleoplasm, enhanced HDAC2 occupation on VHL and VDAC1 promoter regions, and finally accelerated glycolysis and glutaminolysis. Depletion of EPB41L4A-AS1 increased the sensitivity of tumor to glutaminase inhibitor in tumor therapy.Interpretation: EPB41L4A-AS1 functions as a repressor of the Warburg effect and plays important roles in metabolic reprogramming of cancer. (c) 2019 Published by Elsevier B.V.