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Long Noncoding RNA DANCR Regulates Proliferation and Migration by Epigenetically Silencing FBP1 in Tumorigenesis of Cholangiocar

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Long Noncoding RNA DANCR Regulates Proliferation and Migration by Epigenetically Silencing FBP1 in Tumorigenesis of Cholangiocar Wang et al. Cell Death and Disease (2019) 10:585 https://doi.org/10.1038/s41419-019-1810-z Cell Death & Disease ARTICLE Open Access Long noncoding RNA DANCR regulates proliferation and migration by epigenetically silencing FBP1 in tumorigenesis of cholangiocarcinoma Ni Wang1, Chongguo Zhang2, Wulin Wang3,JieLiu4,YangYu1,YouLi5, Mingjiong Zhang6,XianxiuGe1, Quanpeng Li1 and Lin Miao 1 Abstract Recently, long noncoding RNAs (lncRNAs) have been shown to play significant regulatory roles in human tumorigenesis. However, the biological function of lncRNAs in cholangiocarcinoma (CCA) remains largely unknown. In this study, DANCR was shown to be significantly upregulated in CCA. DANCR regulated the proliferation and migration of CCA cells in vitro. Moreover, downregulation of DANCR suppressed CCA cells proliferation in vivo. RNA-seq revealed that DANCR knockdown preferentially affected genes linked with cell proliferation and cell differentiation. Furthermore, mechanistic investigation validated that DANCR could bind EZH2 and modulate the histone methylation of promoter of FBP1, thereby regulating CCA cells growth and migration. Taken together, these results demonstrated the significant roles of DANCR in CCA and may provide a theoretical basis for clinical diagnosis and treatment of CCA. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Long noncoding RNAs (lncRNAs), the RNA transcripts Cholangiocarcinoma (CCA), an extremely malignant longer than 200 nucleotides with little or no protein- tumor that arises from cholangiocytes, has been a major coding potential4,5, have been shown to exhibit critical health burden worldwide for decades1. Given the lack of function in tumorigenesis, including CCA6,7. In addition, sensitive indicators, the diagnosis of the majority of CCA as a regulator in the process of epigenetics, lncRNAs cases typically occurs at a late stage, resulting that patients could regulate gene expression in chromatin modification, with unresectable tumors only have a median overall transcription and posttranscription process8. For instance, survival <12 months2,3. Therefore, it is imperative to lncRNA HOXC-AS3 promotes GC cell proliferation and identify novel diagnostic and therapeutic targets by deci- migration through modifying the transcription of target phering the carcinogenesis and progression mechanisms genes by an interaction with YBX19. Overexpressed underlying CCA to improve patient survival times. UCA1 could regulate migration and invasion potential of CCA cells through activating AKT/GSK-3β axis to upre- gulate CCND1 expression10. Long noncoding RNA DANCR (Differentiation antag- Correspondence: Lin Miao ([email protected]) onizing nonprotein coding RNA), also known as ANCR or 1Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China SNHG13, is an 855-nucleotide lncRNA located at human 2Department of Oncology, Second Affiliated Hospital, Nanjing Medical chromosome 4q12 and was first identified as a suppressor ’ University, Nanjing, Jiangsu Province, People s Republic of China during epidermal progenitor cell differentiation11. Full list of author information is available at the end of the article. These authors contributed equally: Ni Wang, Chongguo Zhang, Wulin Wang Recently, DANCR has been found to be aberrantly Edited by B. Rotblat © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Wang et al. Cell Death and Disease (2019) 10:585 Page 2 of 11 expressed and play important roles in a variety of control siRNA (si-NC) was purchased from Invitrogen – tumors12 20. However, the expression pattern and the (Invitrogen, CA, USA). DANCR and EZH2 siRNAs were exact role of DANCR in human CCA remain unclear. purchased from Realgene Biotechnology (Nanjing, China). In our present study, we first identified that DANCR The sh-DANCR was cloned into pENTR/U6 vector. The was highly expressed in CCA tissues in comparison with plasmid was transfected into CCA cells using X- normal adjacent controls. In addition, we found that tremeGEN HP DNA Transfection Reagent (Roche, DANCR could regulate cell proliferation and migration Basel, Switzerland) according to the producer’s protocol. in vitro. Moreover, downregulation of DANCR sup- pressed CCA cell proliferation in vivo. RNA-seq analysis Cell proliferation analysis indicated the preference of DANCR to regulate the Cell viability was determined using the CCK-8 Kit expression of genes related to proliferation and migration. (Houston TX, USA) according to the manufacturer’spro- Mechanistic investigations elucidated that DANCR could tocol. In the colony formation test, transfected cells were directly bind to EZH2 and then mediate the H3K27 tri- placed in six-well plates with medium containing 10% FBS. methylation in promoter region of Fructose-1, 6- After 14 days, colonies were fixed with methanol and stained biphosphatase (FBP1) to inhibit the expression of FBP1, with 0.1% crystal violet (Sigma). The stained colonies were thus facilitating CCA tumorigenesis. counted. Edu assays were performed using the Edu Cell Proliferation Assay Kit (Ribobio, Guangzhou, China) fol- Materials and methods lowing the manufacturer’s instructions. Then, the percen- Tissue gathering and ethics statement tages of Edu-positive cells were examined in the sample. All This study analyzed 17 CCA patients undergoing sur- experiments were performed in biological triplicates. gical treatment in the Second Affiliated Hospital of Nanjing Medical University. All specimens were imme- Cell migration assays diately frozen with preservative liquid and stored in liquid For migration assays, 3 × 104 transfected cells in media nitrogen until RNA extraction. The Research Ethics with 1% FBS were added to the upper insertion chamber Committee of Nanjing Medical University (Nanjing, (Millipore, Billerica, MA, USA), while the lower chamber Jiangsu, PR China) approved our study. Written informed contained the medium with 10% FBS. After incubation for consent was obtained from all patients. 24 h, the remaining cells on the upper membrane were removed with a cotton swab. Cells migrating through the RNA extraction and qRT-PCR analysis membrane were dyed with methanol, stained with 0.1% Total RNA was extracted from tissues or cultured cells crystal violet, and imaged with an IX71 inverted microscope using TRIzol reagents (Invitrogen, Carlsbad, CA, USA) (Olympus, Tokyo, Japan). All wells were assessed thrice. according to the manufacturer’s instructions. RNA (1 µg) was then reversely transcribed into cDNA through a Western blot assay and antibodies Reverse Transcription Kit (Takara, Dalian, China). SYBR Cells protein lysates assessed by 10% sodium dodecyl Green (Takara, Dalian China) was used for real-time PCR sulfate-polyacrylamide gel electrophoresis were trans- analysis. The results were normalized to the expression of ferred to nitrocellulose membranes (Sigma-Aldrich, St glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The Louis, MO) for incubation with specific antibodies. ECL primer sequences are listed in Supplementary Table S1. chromogenic substrates were measured by a density meter (Quantity One software; Bio-Rad). GAPDH anti- Cell culture body was used as the control. Anti-EZH2 was purchased CCA cell lines HuCCT1 and RBE were received from the from Proteintech (Wuhan, China), and anti-FBP1 was Institute of Biochemistry and Cell Biology of the Chinese purchased from Abcam (Cambridge, UK). Academy of Sciences (Shanghai, China). Cell lines were cultured in DMEM (Life Technologies, Grand Island, NY, Flow cytometric analysis USA), which contained 10% fetal bovine serum (FBS) After 48 h of transfection with si-NC or si-DANCR, (ScienCell, Carlsbad, CA, USA), 100 mg/mL streptomycin, HuCCT1 and RBE cells were harvested by trypsinization. and 100 U/mL penicillin (Invitrogen, Shanghai, China), in After double staining with fluorescein isothiocyanate air with 5% CO2 and humidity at 37 °C. (FITC)-Annexin V and propidium iodide (BD Biosciences, Franklin Lakes, NJ, USA), the cells were analyzed by flow Cell transfection cytometry (FACScan; BD Biosciences). CCA cells were transfected with particular siRNAs using lipofectamine2000 (Invitrogen, CA, USA) based on In vivo tumor formation assays the manufacturer’s instructions. Cells were harvested for Four-week-old athymic male mice purchased from the analyses 48 h after transfections. Scrambled negative Animal Center of Nanjing University (Nanjing, China) Official journal of the Cell Death Differentiation Association Wang et al. Cell Death and Disease (2019) 10:585 Page 3 of 11 were maintained under certain pathogen-free
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