Nuclear-Encoded lncRNA MALAT1 Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway.
Nuclear-Encoded lncRNA MALAT1 Epigenetically Controls Metabolic Reprogramming in HCC Cells through the Mitophagy Pathway.
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核编码的 lncRNA MALAT1 通过线粒体自噬途径表观遗传控制 HCC 细胞的代谢重编程
DOI：
10.1016/j.omtn.2020.09.040
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发表时间：
2021-03-05
期刊：
影响因子：
--
通讯作者：
Cui J
中科院分区：
文献类型：
--
作者：
Zhao Y;Zhou L;Li H;Sun T;Wen X;Li X;Meng Y;Li Y;Liu M;Liu S;Kim SJ;Xiao J;Li L;Zhang S;Li W;Cohen P;Hoffman AR;Hu JF;Cui J
线粒体功能障碍是癌细胞的代谢标志。在寻找参与肝细胞癌（HCC）中这种失调的分子因素时，我们发现核编码的长非编码RNA（lncRNA）MALAT 1（转移相关肺腺癌转录本1）异常地富集在肝癌细胞的线粒体中。使用RNA逆转录相关陷阱测序（RAT-seq），我们发现MALAT 1与线粒体DNA（mtDNA）上的多个位点相互作用，包括D-loop，COX 2，ND 3和CYTB基因。MALAT 1敲低诱导线粒体DNA和线粒体转录组的CpG甲基化改变。这与线粒体功能的多种异常有关，包括线粒体结构改变、低氧化磷酸化（OXPHOS）、ATP产生减少、线粒体自噬减少、mtDNA拷贝数减少和线粒体凋亡激活。线粒体代谢的这些改变与肿瘤表型的变化以及细胞线粒体自噬、线粒体凋亡和表观遗传调控相关的途径的变化有关。我们进一步表明，RNA穿梭蛋白HuR和线粒体跨膜蛋白MTCH 2介导了MALAT 1在这种核-线粒体串扰中的转运。该研究首次证明了核基因组编码的lncRNA MALAT 1在肝癌细胞线粒体代谢调控中起着重要的表观遗传作用，为进一步阐明lncRNA在肿瘤代谢重编程中的作用奠定了基础。这项研究确定了核基因组编码的lncRNA MALAT 1是一种核到线粒体的表观遗传信使，通过调节肝细胞癌细胞中的线粒体功能来控制代谢重编程。
Mitochondrial dysfunction is a metabolic hallmark of cancer cells. In search of molecular factors involved in this dysregulation in hepatocellular carcinoma (HCC), we found that the nuclear-encoded long noncoding RNA (lncRNA) MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was aberrantly enriched in the mitochondria of hepatoma cells. Using RNA reverse transcription-associated trap sequencing (RAT-seq), we showed that MALAT1 interacted with multiple loci on mitochondrial DNA (mtDNA), including D-loop, COX2, ND3, and CYTB genes. MALAT1 knockdown induced alterations in the CpG methylation of mtDNA and in mitochondrial transcriptomes. This was associated with multiple abnormalities in mitochondrial function, including altered mitochondrial structure, low oxidative phosphorylation (OXPHOS), decreased ATP production, reduced mitophagy, decreased mtDNA copy number, and activation of mitochondrial apoptosis. These alterations in mitochondrial metabolism were associated with changes in tumor phenotype and in pathways involved in cell mitophagy, mitochondrial apoptosis, and epigenetic regulation. We further showed that the RNA-shuttling protein HuR and the mitochondria transmembrane protein MTCH2 mediated the transport of MALAT1 in this nuclear-mitochondrial crosstalk. This study provides the first evidence that the nuclear genome-encoded lncRNA MALAT1 functions as a critical epigenetic player in the regulation of mitochondrial metabolism of hepatoma cells, laying the foundation for further clarifying the roles of lncRNAs in tumor metabolic reprogramming. This study identified the nuclear genome-encoded lncRNA MALAT1 as a nucleus-to-mitochondria epigenetic messenger that controls metabolic reprogramming by regulating mitochondrial function in hepatocellular carcinoma cells.
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
Nature reviews. Cancer
影响因子：
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DOI：
10.4331/wjbc.v6.i3.148
发表时间：
2015-08-26
期刊：
World journal of biological chemistry
影响因子：
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