LncRNA TUG1 sponges miR-145 to promote cancer progression and regulate glutamine metabolism via Sirt3/GDH axis

Long noncoding RNAs (lncRNAs) are important regulators in cancer progression. Deregulation of the lncRNA taurine upregulated gene 1 (TUG1) predicts poor prognosis and is implicated in the development of several cancers. In this study, we investigated the role of TUG1 in the pathogenesis of intrahepatic cholangiocarcinoma (ICC). We found that TUG1 is upregulated in ICC samples, which correlates with poor prognosis and adverse clinical pathological characteristics. Knockdown of TUG1 inhibited the proliferation, motility, and invasiveness of cultured ICC cells, and decreased tumor burden in a xenograft mouse model. When we explored the mechanisms underlying these effects, we found that TUG1 acts as an endogenous competing RNA (ceRNA) that ‘sponges’ miR-145, thereby preventing the degradation of Sirt3 mRNA and increasing expression of Sirt3 and GDH proteins. Accordingly, glutamine consumption, α-KG production, and ATP levels were dramatically decreased by TUG1 knockdown in ICC cells, and this effect was reversed by miR-145 inhibition. These findings indicate that the TUG1/miR-145/Sirt3/GDH regulatory network may provide a novel therapeutic strategy for treatment of ICC.

[1]  Xiaodong Song,et al.  Analysing the relationship between lncRNA and protein-coding gene and the role of lncRNA as ceRNA in pulmonary fibrosis , 2014, Journal of cellular and molecular medicine.

[2]  Xinwei Han,et al.  Long Noncoding RNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation and Invasion in Gastric Cancer via Negatively Modulating miRNA-145-5p , 2017, Oncology research.

[3]  R. Kong,et al.  P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression , 2014, Cell Death and Disease.

[4]  Zheng Li,et al.  TUG1: a pivotal oncogenic long non‐coding RNA of human cancers , 2016, Cell proliferation.

[5]  Prahlad T. Ram,et al.  Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer , 2014, Molecular systems biology.

[6]  Longyang Jin,et al.  Long non-coding RNA TUG1 promotes cell proliferation and metastasis by negatively regulating miR-300 in gallbladder carcinoma. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[7]  S. Hanash,et al.  Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2. , 2016, Molecular cell.

[8]  Jennifer B Dennison,et al.  Long Noncoding RNA Ceruloplasmin Promotes Cancer Growth by Altering Glycolysis. , 2015, Cell reports.

[9]  James J. Driscoll,et al.  Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer , 2014, Oncotarget.

[10]  J. Gray,et al.  Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. , 2013, Cancer cell.

[11]  H. Cai,et al.  Long non-coding RNA taurine upregulated 1 enhances tumor-induced angiogenesis through inhibiting microRNA-299 in human glioblastoma , 2017, Oncogene.

[12]  Jungwon Choi,et al.  Autophagy is required for PDAC glutamine metabolism , 2016, Scientific Reports.

[13]  G. Gores,et al.  Clinical diagnosis and staging of cholangiocarcinoma , 2011, Nature Reviews Gastroenterology &Hepatology.

[14]  R. Kurokawa,et al.  Long Noncoding RNAs , 2015, Springer Japan.

[15]  Guang-hui Xu,et al.  Long non-coding RNA TUG1 promotes cell proliferation and metastasis in human breast cancer , 2017, Breast Cancer.

[16]  M. Gazouli,et al.  Expression of microRNAs, miR‐21, miR‐31, miR‐122, miR‐145, miR‐146a, miR‐200c, miR‐221, miR‐222, and miR‐223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance , 2013, Molecular carcinogenesis.

[17]  M. Dinger,et al.  Endogenous microRNA sponges: evidence and controversy , 2016, Nature Reviews Genetics.

[18]  P. Overbeek,et al.  Long noncoding RNA Tug1 regulates mitochondrial bioenergetics in diabetic nephropathy. , 2016, The Journal of clinical investigation.

[19]  Ying Zhang,et al.  Long non-coding RNA TUG1 promotes endometrial cancer development via inhibiting miR-299 and miR-34a-5p , 2017, Oncotarget.

[20]  John M. Asara,et al.  Glutamine supports pancreatic cancer growth through a Kras-regulated metabolic pathway , 2013, Nature.

[21]  Maite Huarte.  The emerging role of lncRNAs in cancer , 2015, Nature Medicine.

[22]  Liyong Pu,et al.  MiR-145 functions as a tumor suppressor targeting NUAK1 in human intrahepatic cholangiocarcinoma. , 2015, Biochemical and biophysical research communications.

[23]  Glutamate dehydrogenase is a novel prognostic marker and predicts metastases in colorectal cancer patients , 2015, Journal of Translational Medicine.

[24]  C. Steegborn,et al.  Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. , 2008, Journal of molecular biology.

[25]  Haiyang Xie,et al.  Coding-noncoding gene expression in intrahepatic cholangiocarcinoma. , 2016, Translational research : the journal of laboratory and clinical medicine.

[26]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[27]  Sergio Capaccioli,et al.  A pathophysiological view of the long non-coding RNA world , 2014, Oncotarget.

[28]  Jian-jun Peng,et al.  Long non-coding RNA TUG1 promotes colorectal cancer metastasis via EMT pathway , 2016, Oncotarget.

[29]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[30]  S. Srivastava,et al.  A long noncoding RNA connects c-Myc to tumor metabolism , 2014, Proceedings of the National Academy of Sciences.

[31]  Kaifeng Qiu,et al.  Double‐negative feedback loop between long non‐coding RNA TUG1 and miR‐145 promotes epithelial to mesenchymal transition and radioresistance in human bladder cancer cells , 2015, FEBS letters.

[32]  Huan Pang,et al.  Long non-coding RNA UCA1 promotes glutamine metabolism by targeting miR-16 in human bladder cancer. , 2015, Japanese journal of clinical oncology.

[33]  X. Kong,et al.  Long Noncoding RNA GCASPC, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase-Dependent Cell Proliferation in Gallbladder Cancer. , 2016, Cancer research.

[34]  Y. Totoki,et al.  Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment , 2016, Nature Communications.

[35]  Howard Y. Chang,et al.  Long Noncoding RNAs: Cellular Address Codes in Development and Disease , 2013, Cell.

[36]  J. Blenis,et al.  Regulates Glutamine Metabolism through the eIF 4 B-Dependent Control of c-Myc Translation , 2014 .

[37]  P. Pandolfi,et al.  The multilayered complexity of ceRNA crosstalk and competition , 2014, Nature.

[38]  G. Ren,et al.  LncRNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation by Inhibiting MicroRNA-9 in MCF-7 Cells , 2016, Journal of breast cancer.

[39]  A. Levine,et al.  Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function , 2010, Proceedings of the National Academy of Sciences.

[40]  C. Cepko,et al.  The Noncoding RNA Taurine Upregulated Gene 1 Is Required for Differentiation of the Murine Retina , 2005, Current Biology.