A reciprocal feedback between N6-methyladenosine reader YTHDF3 and lncRNA DICER1-AS1 promotes glycolysis of pancreatic cancer through inhibiting maturation of miR-5586-5p.
A reciprocal feedback between N6-methyladenosine reader YTHDF3 and lncRNA DICER1-AS1 promotes glycolysis of pancreatic cancer through inhibiting maturation of miR-5586-5p.
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N6-甲基腺苷阅读器 YTHDF3 和 lncRNA DICER1-AS1 之间的相互反馈通过抑制 miR-5586-5p 的成熟促进胰腺癌的糖酵解。
DOI：
10.1186/s13046-022-02285-6
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发表时间：
2022-02-19
期刊：
影响因子：
--
通讯作者：
Zhao G
中科院分区：
文献类型：
--
作者：
Hu Y;Tang J;Xu F;Chen J;Zeng Z;Han S;Wang F;Wang D;Huang M;Zhao Y;Huang Y;Zhuo W;Zhao G
糖酵解是肿瘤发生代谢重编程的关键过程。先前的研究表明，lncRNA 可能在各种肿瘤的糖酵解中发挥关键作用。然而，lncRNA在胰腺癌糖酵解中的功能尚未完全阐明。应用生物信息分析揭示潜在的糖酵解相关lncRNA。采用RT-PCR和荧光原位杂交（FISH）检测胰腺癌组织和细胞系中DICER1反义RNA1（DICER1-AS1）的表达。进行功能获得和丧失实验来评估 DICER1-AS1 在 PC 糖酵解和肿瘤发生中的作用。通过荧光素酶报告基因检测、RNA免疫沉淀（RIP）和染色质免疫沉淀（ChIP）等机制实验揭示了DICER1-AS1在PC糖酵解中的下游靶点和调控机制。生物信息分析表明DICER1-AS1在PC中表达下调，且与糖酵解基因表达呈负相关。同时，DICER1-AS1的过表达在体外和体内均抑制PC细胞的糖酵解、增殖和转移。从机制上讲，DICER1-AS1 通过将转录因子 YY1 招募到 DICER1 启动子来促进其正义基因 DICER1 的转录。同时，DICER1 促进 miR-5586-5p 成熟，从而抑制糖酵解基因表达，包括 LDHA、HK2、PGK1 和 SLC2A1。值得注意的是，N6-甲基腺苷 (m6A) 读取器 YTHDF3 和 DICER1-AS1 之间的相互作用增强，导致 DICER1-AS1 响应葡萄糖消耗而降解。此外，我们的数据显示，YTHDF3 是 miR-5586-5p 的关键靶标，通过与 DICER1-AS1 形成负反馈来调节 PC 的糖酵解。我们的结果表明 m6A 阅读器 YTHDF3 和糖酵解 lncRNA DICER1-AS1 的负反馈参与 PC 的糖酵解和肿瘤发生。在线版本包含可在 10.1186/s13046-022-02285-6 获取的补充材料。
Glycolysis is a pivotal process in metabolic reprogramming of tumorigenesis. Previous research has indicated that lncRNAs might play crucial roles in glycolysis of various tumors. However, the function of lncRNAs in glycolysis of pancreatic cancer has not been fully elucidated. Bio-information analyses were applied to reveal the potential glycolysis-associated lncRNA. RT-PCR and fluorescence in situ hybridization (FISH) assays were applied to detect the expression of antisense RNA1 of DICER1 (DICER1-AS1) in pancreatic cancer tissues and cell lines. Gain- and loss-of-function experiments were performed to evaluate the roles of DICER1-AS1 in glycolysis and tumorigenesis of PC. Mechanistic experiments including luciferase reporter assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) were employed to uncover the downstream targets and regulatory mechanism of DICER1-AS1 in glycolysis of PC. Bio-information analysis indicated that DICER1-AS1 was downregulated in PC and negatively correlated with glycolytic genes expression. Meanwhile, overexpression of DICER1-AS1 inhibited glycolysis, proliferation, and metastasis of PC cells both in vitro and in vivo. Mechanistically, DICER1-AS1 promoted transcription of its sense gene DICER1 by recruiting transcriptional factor YY1 to the DICER1 promoter. Meanwhile, DICER1 promoted maturation of miR-5586-5p which consequently inhibited glycolytic gene expression including LDHA, HK2, PGK1, and SLC2A1. Notably, enhanced interaction between N6-methyladenosine (m6A) reader YTHDF3 and DICER1-AS1 led to degradation of DICER1-AS1 in response to glucose depletion. Moreover, our data revealed that YTHDF3 was a critical target for miR-5586-5p, by which forming a negative feedback with DICER1-AS1 to regulate glycolysis of PC. Our results implicate a negative feedback of m6A reader YTHDF3 and glycolytic lncRNA DICER1-AS1 is involved in glycolysis and tumorigenesis of PC. The online version contains supplementary material available at 10.1186/s13046-022-02285-6.
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影响因子：
14.9
作者：
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