Nutrient Stress-Dysregulated Antisense lncRNA GLS-AS Impairs GLS-Mediated Metabolism and Represses Pancreatic Cancer Progression
Nutrient Stress-Dysregulated Antisense lncRNA GLS-AS Impairs GLS-Mediated Metabolism and Represses Pancreatic Cancer Progression
复制标题
营养应激失调的反义 lncRNA GLS-AS 损害 GLS 介导的代谢并抑制胰腺癌进展。
DOI：
10.1158/0008-5472.can-18-0419
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发表时间：
2019-04-01
期刊：
影响因子：
11.2
通讯作者：
Zhao, Gang
中科院分区：
文献类型：
--
作者：
Deng, Shi-Jiang;Chen, Heng-Yu;Zhao, Gang
众所周知，癌细胞会经历代谢重新编程，如糖酵解和谷氨酰胺成瘾，以维持快速增殖和转移。目前尚不清楚长非编码RNA(LncRNA)是否协调了胰腺癌中的代谢转换。在这里，我们发现了一个富含核的反义谷氨酰胺酶(GLS-AS)，它是参与胰腺癌新陈代谢的关键调节因子。与非癌旁组织相比，GLS-AS在胰腺癌组织中表达下调。去除GLS-AS可促进胰腺癌细胞在体外和裸鼠移植瘤中的增殖和侵袭。GLS-AS通过依赖于ADAR/DICER的RNA干扰，与GLS前-mRNA形成双链RNA，在转录后水平抑制GLS的表达。营养胁迫诱导的Myc在转录水平下调GLS-AS的表达。相反，GLS-AS通过破坏GLS介导的Myc蛋白的稳定性而降低Myc的表达。这些结果表明，在营养胁迫过程中，Myc和GLS-AS调节GLS的过度表达是一个相互反馈的循环。异位过表达GLS-AS通过抑制Myc/GLS途径抑制胰腺癌细胞的增殖和侵袭。此外，在胰腺癌的临床标本中，GLS-AS和GLS的表达呈负相关，而GLS-AS的低表达与临床预后不良有关。总之，我们的研究揭示了一种新的lncRNA介导的Myc/Gls途径，该途径可能作为胰腺癌治疗的代谢靶点，并促进了我们对lncRNA在营养应激和肿瘤发生中的耦合作用的理解。意义：这些发现表明，lncRNA GLS-AS介导了Myc和Gls的反馈循环，为胰腺癌的代谢重新编程提供了一个潜在的治疗靶点。图表摘要：http://cancerres.aacrjournals.org/content/canres/79/7/1398/F1.大号的。见Mafra和Dias的相关评论，第1302页
Cancer cells are known to undergo metabolic reprogramming, such as glycolysis and glutamine addiction, to sustain rapid proliferation and metastasis. It remains undefined whether long noncoding RNAs (lncRNA) coordinate the metabolic switch in pancreatic cancer. Here we identify a nuclear-enriched antisense lncRNA of glutaminase (GLS-AS) as a critical regulator involved in pancreatic cancer metabolism. GLS-AS was down-regulated in pancreatic cancer tissues compared with noncancerous peritumor tissues. Depletion of GLS-AS promoted proliferation and invasion of pancreatic cancer cells both in vitro and in xenograft tumors of nude mice. GLS-AS inhibited GLS expression at the posttranscriptional level via formation of double stranded RNA with GLS pre-mRNA through ADAR/Dicer-dependent RNA interference. GLS-AS expression was transcriptionally downregulated by nutrient stress-induced Myc. Conversely, GLS-AS decreased Myc expression by impairing the GLS-mediated stability of Myc protein. These results imply a reciprocal feedback loop wherein Myc and GLS-AS regulate GLS overexpression during nutrient stress. Ectopic overexpression of GLS-AS inhibited proliferation and invasion of pancreatic cancer cells by repressing the Myc/GLS pathway. Moreover, expression of GLS-AS and GLS was inversely correlated in clinical samples of pancreatic cancer, while low expression of GLS-AS was associated with poor clinical outcomes. Collectively, our study implicates a novel lncRNA-mediated Myc/GLS pathway, which may serve as a metabolic target for pancreatic cancer therapy, and advances our understanding of the coupling role of lncRNA in nutrition stress and tumorigenesis.Significance: These findings show that lncRNA GLS-AS mediates a feedback loop of Myc and GLS, providing a potential therapeutic target for metabolic reprogramming in pancreatic cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1398/F1. large. jpg.See related commentary by Mafra and Dias, p. 1302