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Nutrient Stress–Dysregulated Antisense Lncrna GLS-AS Impairs

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Nutrient Stress–Dysregulated Antisense Lncrna GLS-AS Impairs Published OnlineFirst December 18, 2018; DOI: 10.1158/0008-5472.CAN-18-0419 Cancer Molecular Cell Biology Research Nutrient Stress–Dysregulated Antisense lncRNA GLS-AS Impairs GLS-Mediated Metabolism and Represses Pancreatic Cancer Progression Shi-Jiang Deng1, Heng-Yu Chen1, Zhu Zeng1, Shichang Deng1, Shuai Zhu1, Zeng Ye1, Chi He1, Ming-Liang Liu1, Kang Huang1, Jian-Xin Zhong1, Feng-Yu Xu1, Qiang Li1, Yang Liu1, Chunyou Wang2, and Gang Zhao1 Abstract Cancer cells are known to undergo metabolic Normal Nutrient stress reprogramming, such as glycolysis and glutamine AAAAAA addiction, to sustain rapid proliferation and AAAAAA metastasis. It remains undefined whether long GLS pre–mRNA noncoding RNAs (lncRNA) coordinate the meta- bolic switch in pancreatic cancer. Here we identify GLS pre–mRNA GLS protein ADAR1–dicer a nuclear-enriched antisense lncRNA of glutamin- Degradation ADAR1–dicer Degradation GLS–AS ase (GLS-AS) as a critical regulator involved in GLS–AS pancreatic cancer metabolism. GLS-AS was down- GLS–AS gene Myc regulated in pancreatic cancer tissues compared GLS–AS gene with noncancerous peritumor tissues. Depletion Nutrient stress promotes accumulation of Myc. Myc inhibits transcription of the antisense lncRNA of glutaminase (GLS–AS), leading of GLS-AS promoted proliferation and invasion of to GLS elevation and stabilization of Myc. pancreatic cancer cells both in vitro and in xenograft © 2018 American Association for Cancer Research tumors of nude mice. GLS-AS inhibited GLS expression at the posttranscriptional level via for- mation 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. XXX Introduction of these addictions is "Warburg effect" that cancer cells tend to take advantage of glucose via "aerobic glycolysis" pathway, Recent studies have shown that cancer cells exhibit metabolic eveninthepresenceofoxygen(1).Asanoutcome,thepyruvate dependencies to distinguish them from normal tissues. One generated via the aerobic glycolysis is converted to lactic acid, but not acetyl-CoA. To compensate for the insufficient citric 1Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2Deparment of acid cycle, cancer cells often activate glutamine metabolism (2). Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University Therefore, markedly aggravated glucose and glutamine deple- of Science and Technology, Wuhan, China. tion may happen in tumor cells as there are inadequacies Note: Supplementary data for this article are available at Cancer Research between vascular supply and metabolic requirement (3). Such Online (http://cancerres.aacrjournals.org/). a situation is especially distinct in pancreatic cancer, where S.-J. Deng, H.-Y. Chen, and Z. Zeng contributed equally to this article. glucose and glutamine metabolism is reprogrammed by onco- – Corresponding Author: Gang Zhao, Department of Emergency Surgery, Union genic Kras to support cancer cell growth (4 6). Therefore, Hospital, Tongji Medical College, Huazhong University of Science and Technol- the metabolic characteristics and distinct hypovascular of ogy, Wuhan 430022, China. Phone: 8627-8535-1621; Fax: 8627-8535-1669; pancreatic cancer would lead to a dramatic nutrients stress E-mail: [email protected] especially caused by glucose and glutamine depletion (7). In doi: 10.1158/0008-5472.CAN-18-0419 fact, such a paradoxical condition affords pathway to rapidly Ó2018 American Association for Cancer Research. produce the energy and metabolites required for cancer cells' www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst December 18, 2018; DOI: 10.1158/0008-5472.CAN-18-0419 Deng et al. proliferation, which makes it correlatively resistant to meta- Materials and Methods bolic stress including hypoxia and nutrient deprivation (8). Patients and specimens Data from Yun and colleagues suggest that glucose deprivation The clinical tissues were obtained from Pancreatic Disease can drive the acquisition of Kras pathway mutations (9), which Institute of Union Hospital from May 2016 to March 2017. We commonly occurs in pancreatic cancer. The results suggested randomly selected 30 pairs of pancreatic cancer and correspond- that glucose deprivation increases VEGF mRNA stability, which ing nontumor tissues from patients without chemotherapy or might facilitate tumor angiogenesis (10). Furthermore, results radiotherapy before operation. Procedures performed on those from Dejure and colleagues showed glutamine deprivation patients included pancreatectomy or palliative surgery including only halted the proliferation of colon cancer cells, but not I125 seed implantation as well as gastroenterostomy and chole- killed them (11). Notably, nutrient deprivation has been cor- dochojejunostomy according to the National Comprehensive related with poor patient survival, suggesting that instead of Cancer Network (NCCN 2012) guideline for pancreatic cancer. killing the tumor, the scarcity of nutrients can make the cancer The samples were obtained from surgical resection of patients or cell stronger (12). Therefore, it is crucial to investigate the biopsy of the palliative surgery patients. The study was conducted mechanisms that are required to accommodate nutrient stresses in accordance with the Declaration of Helsinki. All samples were as an alternative strategy for the therapeutic treatment of pan- collected with the written informed consent of the patients, and creatic cancer. the study was approved by the local Research Ethics Committee at Long noncoding RNAs (lncRNA) are a major class of tran- the Academic Medical Center of Huazhong University of Science scripts, longer than 200 nt, and lack protein-coding potential. and Technology (Wuhan, China). Accumulating evidence suggests that lncRNAs are dysregulated in cancers and involved in the development of cancers (13). Cell culture fi Speci cally, recent results have demonstrated a link between BxPC-3 and PANC-1 cells were obtained from ATCC. They were lncRNAs and altered metabolism in cancers. A study reported tested and authenticated for genotypes by DNA fingerprinting that a glucose starvation–induced lncRNA-NBR2 reciprocally within 6 months. Cells were cultured in 5% CO2 at 37 C and activates AMPK pathway in response to energy stress (14). grown in complete medium, which was composed of 90% LncRNA-UCA1 promotes glycolysis in bladder cancer cells RPMI1640 (Gibco), 10% FBS (Gibco), 100 U/mL penicillin, and by activating the cascade of mTOR-STAT3/miR143-HK2 (15). 100 mg/mL streptomycin. To build nutrition deprivation model, Results from Ellis and colleagues suggested that insulin/IGF we incubated cells with complete medium without glutamine – signaling repressed lncRNA-CRNDE promotes aerobic glyco- [Glutamine (À)] or complete medium with 1 mmol/L glucose lysis of cancer cells (16). LncRNA-ANRIL is upregulated in [Glucose (À)]. RPMI1640 having no glutamine or glucose was nasopharyngeal carcinoma and promotes cancer progression purchased from Gibco. via increasing glucose uptake for glycolysis (17). In addition, lncR-UCA1 was found to reduce ROS production, and pro- RNA FISH moted mitochondrial glutaminolysis in human bladder can- To detect GLS-AS and GLS pre-mRNAs, we purchased a kit fi cer (18). Nevertheless, the speci c lncRNAs, which couple named FISH Tag RNA Multicolor Kit from Invitrogen to perform nutrient stress and pancreatic cancer, have not been elucidated FISH. The probe synthesis, labeling, and purification procedures – yet. In this study, we endeavored to discover a nutrient stress were performed according to the manufacturer's instructions. responsive lncRNA that is involved in the pancreatic cancer The probe-identified GLS pre-mRNA (Probe1) was labeled with progression. green fluorescence, and the GLS-AS probe (Probe2) was labeled Glutaminase (GLS) is a phosphate-activated amidohydrolase with red fluorescence. Cells were fixed in formaldehyde, perme- that catalyzes the hydrolysis of glutamine to glutamate and abilized by Triton X-100, and then hybridization was carried out ammonia to support metabolism homeostasis, bioenergetics, using labeled probes in a moist chamber at 42C overnight. If and nitrogen balance (19). Recent studies
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