组蛋白去乙酰化酶SIRT1对胰腺癌代谢的调控作用

Regulatory role of histone deacetylase SIRT1 in pancreatic cancer metabolism

目的通过代谢组学和转录组学技术,探讨组蛋白去乙酰化酶SIRT1对胰腺癌代谢的调控作用及其作用机制。方法分析TCGA、GTEx和HPA等数据库中胰腺癌和正常组织的数据,鉴定SIRT1的表达。构建6组SIRT1稳定敲减和对照的胰腺癌PANC-1细胞系,分别应用UHPLC-MS/MS和高通量RNA-seq技术测量代谢物和基因表达水平。探索差异代谢物参与的代谢通路及与药物反应性和耐药性的关系。结果TCGA和GTEx数据分析发现,SIRT1在胰腺癌中的表达显著高于正常组织;HPA数据库进一步证实了SIRT1蛋白的高表达。非靶向代谢组检测和高通量转录组测序分别鉴定出59个代谢物和688个基因的差异有统计学意义。差异代谢物主要富集在癌症中胆碱的代谢、嘧啶代谢、ABC转运等代谢通路。有14个显著差异的基因参与了SIRT1调控的代谢通路。这些基因主要富集在嘌呤代谢信号通路,参与ATP结合和小分子代谢等生物过程。CARE分析显示,SIRT1高表达会促使大量抗肿瘤药物出现高反应性,同时也会使部分药物出现耐药性。结论SIRT1对胰腺癌代谢有调控作用,为SIRT1参与胰腺癌代谢的调控机制研究和胰腺癌的靶向治疗奠定了基础。

Objective To explore the regulatory role and mechanism of silent mating-type information regulation 2 homolog 1(SIRT1)in pancreatic cancer metabolism with metabolomic and transcriptomic techniques.Methods RNA-seq data of pancreatic cancer and normal pancreas tissues from TCGA,GTEx,and HPA were analyzed to identify the expression of SIRT1.A total of 6 pairs of SIRT1 knockdown and control groups of pancreatic cancer PANC-1 cell lines were constructed.The metabolite profiles and gene expression profiles were measured using ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)and high-throughput RNA-seq,respectively.Metabolic pathways with significantly different metabolites involved were enriched.The relationship between SIRT1 gene expression and drug responsiveness and drug resistance was analyzed.Results Analysis of TCGA and GTEx data revealed that SIRT1 expression was significantly higher in pancreatic cancer than in normal pancreas tissues;immunohistochemical data from the HPA database further confirmed the higher expression of SIRT1 at the protein level.Untargeted metabolomics and high-throughput RNA-seq identified 59 statistically significantly different metabolites and 688 differentially expressed genes.The differential metabolites were mainly enriched in metabolic pathways such as choline metabolism in cancer,pyrimidine metabolism,and ABC transporters.Fourteen differentially expressed genes were involved in SIRT1-regulated metabolic pathways.These genes were mainly enriched in purine metabolic signaling pathways and involved in biological processes such as ATP binding and small molecule metabolism.CARE online tool showed that higher expression of SIRT1 led to higher responsiveness to many antitumor drugs and resistance to some antitumor drugs.Conclusion Our study reveals that SIRT1 has a regulatory role in pancreatic cancer metabolism,which paves the way for future study on the regulatory mechanism of SIRT1 and targeted therapy for pancreatic cancer.