Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2016

Open Access 01-12-2016 | Primary research

Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer

Authors: Defeng Qi, Jinhui Li, Biao Que, Jialin Su, Mengxi Li, Chaofeng Zhang, Mei Yang, Guoren Zhou, Weidong Ji

Published in: Cancer Cell International | Issue 1/2016

Login to get access

Abstract

Background

Many long non coding RNAs have been identified as key modulators in cancer development. A lncRNA, DBCCR1-003, derived from the locus of tumor suppressor gene DBCCR1 (deleted in bladder cancer chromosome region 1), has unknown function. In the present study, we explored function and molecular mechanism of DBCCR1-003 in bladder cancer (BC) development.

Methods

We evaluated the expression levels of DBCCR1-003 in tissues and cells with western blot and quantitative real-time polymerase chain reaction. Multiple approaches including chromatin immunoprecipitation assay and RNA immunoprecipitation were used to confirm the direct binding of DBCCR1-003 to DNMT1. The recombinant vector overexpressing DBCCR1-003 was constructed. Cell proliferation assay, colony formation assay and flow cytometric analysis were employed to measure the role of DBCCR1-003 in regulation of cell proliferation, cycle and apoptosis.

Results

Firstly we detected the expression of DBCCR1-003, DBCCR1, DNMT1 (DNA methyltransferase 1) and DNA methylation in the promoter of DBCCR1. We found low expression of DBCCR1-003, same as DBCCR1, while high expression of DNMT1 and hypermethylation of DBCCR1 gene promoter in BC tissues and T24 cells line. Further studies revealed that treatment of DNMT inhibitor, 5-aza-2-deoxycytidine(DAC), or overexpression of DBCCR1-003 led to increased DBCCR1 expression by reversion of promoter hypermethylation and DNMT1 binding to DBCCR1 promoter in T24 cells. Importantly, RNA immunoprecipitation (RIP) showed that DBCCR1-003 physically associates with DNMT1. The binding of them was increased with the inhibition of DBCCR1 promoter methylation, indicating that DBCCR1-003 may bind to DNMT1 and prevent DNMT1-mediated the methylation of DBCCR1. Furthermore, overexpression of DBCCR1-003 resulted in significant inhibition of T24 cells growth through the inducing G0/G1 arrest and apoptosis.

Conclusions

Taken together, these findings demonstrated that a novel tumor suppressor DBCCR1-003 regulates the expression of DBCCR1 via binding to DNMT1 and preventing DNMT1-mediated the methylation of DBCCR1 in BC. LncRNA DBCCR1-003 may serve as a novel biomarker and therapeutic target for BC in future cancer clinic.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10(3):155–9.PubMedCrossRef
4.
Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136(4):629–41.PubMedCrossRef
5.
Martens-Uzunova ES, Bottcher R, Croce CM, Jenster G, Visakorpi T, Calin GA. Evolution and functions of long noncoding RNAs. Eur Urol. 2014;65(6):1140–51.PubMedCrossRef
6.
Guil S, Esteller M. Cis-acting noncoding RNAs: friends and foes. Nat Struct Mol Biol. 2012;19(11):1068–75.PubMedCrossRef
7.
8.
Sun M, Jin FY, Xia R, Kong R, Li JH, Xu TP, Liu YW, Zhang EB, Liu XH, De W. Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer. 2014;14:319.PubMedPubMedCentralCrossRef
9.
Takahashi K, Yan IK, Wood J, Haga H, Patel T. Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy. Mol Cancer Res. 2014;12(10):1377–87.PubMedPubMedCentralCrossRef
10.
Ariel I, Sughayer M, Fellig Y, Pizov G, Ayesh S, Podeh D, Libdeh BA, Levy C, Birman T, Tykocinski ML, et al. The imprinted H19 gene is a marker of early recurrence in human bladder carcinoma. Mol Pathol. 2000;53(6):320–3.PubMedPubMedCentralCrossRef
11.
Han Y, Liu Y, Gui Y, Cai Z. Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder. J Surg Oncol. 2013;107(5):555–9.PubMedCrossRef
12.
Xue Y, Ma G, Zhang Z, Hua Q, Chu H, Tong N, Yuan L, Qin C, Yin C, Zhang Z, et al. A novel antisense long noncoding RNA regulates the expression of MDC1 in bladder cancer. Oncotarget. 2015;6(1):484–93.PubMed
13.
He W, Cai Q, Sun F, Zhong G, Wang P, Liu H, Luo J, Yu H, Huang J, Lin T. linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. Biochim Biophys Acta. 2013;1832(10):1528–37.PubMedCrossRef
14.
Cui Z, Ren S, Lu J, Wang F, Xu W, Sun Y, Wei M, Chen J, Gao X, Xu C, et al. The prostate cancer-up-regulated long noncoding RNA PlncRNA-1 modulates apoptosis and proliferation through reciprocal regulation of androgen receptor. Urol Oncol. 2013;31(7):1117–23.PubMedCrossRef
15.
Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell. 2008;32(2):232–46.PubMedCrossRef
16.
17.
Schaukowitch K, Kim TK. Emerging epigenetic mechanisms of long non-coding RNAs. Neuroscience. 2014;264:25–38.PubMedCrossRef
18.
Davis CD, Uthus EO. DNA methylation, cancer susceptibility, and nutrient interactions. Exp Biol Med (Maywood). 2004;229(10):988–95.
19.
Liu L, Wylie RC, Andrews LG, Tollefsbol TO. Aging, cancer and nutrition: the DNA methylation connection. Mech Ageing Dev. 2003;124(10–12):989–98.PubMedCrossRef
20.
Jones PA. DNA methylation errors and cancer. Cancer Res. 1996;56(11):2463–7.PubMed
21.
Laird PW, Jaenisch R. DNA methylation and cancer. Hum Mol Genet. 1994;3:1487–95.PubMed
22.
Scarano MI, Strazzullo M, Matarazzo MR, D’Esposito M. DNA methylation 40 years later: its role in human health and disease. J Cell Physiol. 2005;204(1):21–35.PubMedCrossRef
23.
Yao J, Zhou B, Zhang J, Geng P, Liu K, Zhu Y, Zhu W. A new tumor suppressor LncRNA ADAMTS9-AS2 is regulated by DNMT1 and inhibits migration of glioma cells. Tumour Biol. 2014;35(8):7935–44.PubMedCrossRef
24.
Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo PL, Alberich-Jorda M, Zhang P, et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature. 2013;503(7476):371–6.PubMedPubMedCentralCrossRef
25.
Merry CR, Forrest ME, Sabers JN, Beard L, Gao XH, Hatzoglou M, Jackson MW, Wang Z, Markowitz SD, Khalil AM. DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer. Hum Mol Genet. 2015;24(21):6240–53.PubMedCrossRef
26.
Habuchi T, Luscombe M, Elder PA, Knowles MA. Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33. Genomics. 1998;48(3):277–88.PubMedCrossRef
27.
Habuchi T, Takahashi T, Kakinuma H, Wang L, Tsuchiya N, Satoh S, Akao T, Sato K, Ogawa O, Knowles MA, et al. Hypermethylation at 9q32-33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer. Oncogene. 2001;20(4):531–7.PubMedCrossRef
28.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 1996;93(18):9821–6.PubMedPubMedCentralCrossRef
29.
Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH, Kim JI, Chang SG, Chi SG. Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma. Cancer Res. 2001;61(18):6688–92.PubMed
30.
Kim WJ, Kim EJ, Jeong P, Quan C, Kim J, Li QL, Yang JO, Ito Y, Bae SC. RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors. Cancer Res. 2005;65(20):9347–54.PubMedCrossRef
31.
Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta. 2007;1775(1):138–62.PubMed
32.
Bernardino J, Roux C, Almeida A, Vogt N, Gibaud A, Gerbault-Seureau M, Magdelenat H, Bourgeois CA, Malfoy B, Dutrillaux B. DNA hypomethylation in breast cancer: an independent parameter of tumor progression? Cancer Genet Cytogenet. 1997;97(2):83–9.PubMedCrossRef
33.
Soares J, Pinto AE, Cunha CV, Andre S, Barao I, Sousa JM, Cravo M. Global DNA hypomethylation in breast carcinoma: correlation with prognostic factors and tumor progression. Cancer. 1999;85(1):112–8.PubMedCrossRef
34.
Wang X, Song X, Glass CK, Rosenfeld MG. The long arm of long noncoding RNAs: roles as sensors regulating gene transcriptional programs. Cold Spring Harb Perspect Biol. 2011;3(1):a3756.CrossRef
35.
36.
37.
Zhang Y, Ma M, Liu W, Ding W, Yu H. Enhanced expression of long noncoding RNA CARLo-5 is associated with the development of gastric cancer. Int J Clin Exp Pathol. 2014;7(12):8471–9.PubMedPubMedCentral
38.
Ying L, Huang Y, Chen H, Wang Y, Xia L, Chen Y, Liu Y, Qiu F. Downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer. Mol BioSyst. 2013;9(3):407–11.PubMedCrossRef
39.
Shi Y, Liu Y, Wang J, Jie D, Yun T, Li W, Yan L, Wang K, Feng J. Downregulated long noncoding RNA BANCR promotes the proliferation of colorectal cancer cells via downregulation of p21 Expression. PLoS One. 2015;10(4):e122679.
40.
Ma MZ, Kong X, Weng MZ, Zhang MD, Qin YY, Gong W, Zhang WJ, Quan ZW. Long non-coding RNA-LET is a positive prognostic factor and exhibits tumor-suppressive activity in gallbladder cancer. Mol Carcinog. 2014;54(11):1397–406.PubMedCrossRef
41.
Nakagawa T, Kanai Y, Ushijima S, Kitamura T, Kakizoe T, Hirohashi S. DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis. J Urol. 2005;173(5):1767–71.PubMedCrossRef
42.
Morris KV. Long antisense non-coding RNAs function to direct epigenetic complexes that regulate transcription in human cells. Epigenetics. 2009;4(5):296–301.PubMedPubMedCentralCrossRef
43.
Beckedorff FC, Amaral MS, Deocesano-Pereira C, Verjovski-Almeida S. Long non-coding RNAs and their implications in cancer epigenetics. Biosci Rep. 2013;33(4):667–75.CrossRef
44.
Li Q, Su Z, Xu X, Liu G, Song X, Wang R, Sui X, Liu T, Chang X, Huang D. AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans. Proc Natl Acad Sci USA. 2012;109(35):14110–5.PubMedPubMedCentralCrossRef
45.
46.
Dhawan D, Ramos-Vara JA, Hahn NM, Waddell J, Olbricht GR, Zheng R, Stewart JC, Knapp DW. DNMT1: an emerging target in the treatment of invasive urinary bladder cancer. Urol Oncol. 2013;31(8):1761–9.PubMedCrossRef
47.
Szyf M, Detich N. Regulation of the DNA methylation machinery and its role in cellular transformation. Prog Nucleic Acid Res Mol Biol. 2001;69:47–79.PubMedCrossRef
48.
Wang L, Zhao Y, Bao X, Zhu X, Kwok YK, Sun K, Chen X, Huang Y, Jauch R, Esteban MA, et al. LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration. Cell Res. 2015;25(3):335–50.PubMedPubMedCentralCrossRef
49.
Chalei V, Sansom SN, Kong L, Lee S, Montiel JF, Vance KW, Ponting CP. The long non-coding RNA Dali is an epigenetic regulator of neural differentiation. Elife. 2014;3:e4530.CrossRef
Metadata
Title
Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer
Authors
Defeng Qi
Jinhui Li
Biao Que
Jialin Su
Mengxi Li
Chaofeng Zhang
Mei Yang
Guoren Zhou
Weidong Ji
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2016
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-016-0356-8

Other articles of this Issue 1/2016

Cancer Cell International 1/2016 Go to the issue

Primary research

Inhibition of glycolytic enzyme hexokinase II (HK2) suppresses lung tumor growth

Primary Research

MiR-519d facilitates the progression and metastasis of cervical cancer through direct targeting Smad7

Primary research

Involvement of human chorionic gonadotropin in regulating vasculogenic mimicry and hypoxia-inducible factor-1α expression in ovarian cancer cells

Primary Research

SOX17 increases the cisplatin sensitivity of an endometrial cancer cell line

Primary research

miRNA-135a promotes hepatocellular carcinoma cell migration and invasion by targeting forkhead box O1

Primary research

Comprehensive characterization of the patient-derived xenograft and the paralleled primary hepatocellular carcinoma cell line
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits