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

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Kidney Cancer | Research

RETRACTED ARTICLE: Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

Authors: Wuping Yang, Kenan Zhang, Lei Li, Yawei Xu, Kaifang Ma, Haibiao Xie, Jingcheng Zhou, Lin Cai, Yanqing Gong, Kan Gong

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Login to get access

Abstract

Background

Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear.

Methods

Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level.

Results

ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression.

Conclusions

This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.
Appendix
Available only for authorised users
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.PubMedCrossRef
2.
Frank I, Blute ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H. Independent validation of the 2002 American joint committee on cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort. J Urol. 2005;173(6):1889–92.PubMedCrossRef
3.
Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376(4):354–66.PubMedCrossRef
4.
Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Prim. 2017;3:17009.PubMedCrossRef
5.
Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin. 2017;67(6):507–24.PubMedCrossRef
6.
Reustle A, Di Marco M, Meyerhoff C, Nelde A, Walz JS, Winter S, et al. Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy. Genome Med. 2020;12(1):32.PubMedPubMedCentralCrossRef
7.
Deveson IW, Hardwick SA, Mercer TR, Mattick JS. The dimensions, dynamics, and relevance of the mammalian noncoding Transcriptome. Trends Genetics. 2017;33(7):464–78.CrossRef
8.
Esposito R, Bosch N, Lanzos A, Polidori T, Pulido-Quetglas C, Johnson R. Hacking the Cancer genome: profiling therapeutically actionable long non-coding RNAs using CRISPR-Cas9 screening. Cancer Cell. 2019;35(4):545–57.PubMedCrossRef
9.
10.
11.
Wang G, Zhang ZJ, Jian WG, Liu PH, Xue W, Wang TD, et al. Novel long noncoding RNA OTUD6B-AS1 indicates poor prognosis and inhibits clear cell renal cell carcinoma proliferation via the Wnt/beta-catenin signaling pathway. Mol Cancer. 2019;18(1):15.PubMedPubMedCentralCrossRef
12.
Hamilton MJ, Young M, Jang K, Sauer S, Neang VE, King AT, et al. HOTAIRM1 lncRNA is downregulated in clear cell renal cell carcinoma and inhibits the hypoxia pathway. Cancer Lett. 2020;472:50–8.PubMedCrossRef
13.
Zhai W, Zhu R, Ma J, Gong D, Zhang H, Zhang J, et al. A positive feed-forward loop between LncRNA-URRCC and EGFL7/P-AKT/FOXO3 signaling promotes proliferation and metastasis of clear cell renal cell carcinoma. Mol Cancer. 2019;18(1):81.PubMedPubMedCentralCrossRef
14.
Li JK, Chen C, Liu JY, Shi JZ, Liu SP, Liu B, et al. Long noncoding RNA MRCCAT1 promotes metastasis of clear cell renal cell carcinoma via inhibiting NPR3 and activating p38-MAPK signaling. Mol Cancer. 2017;16(1):111.PubMedPubMedCentralCrossRef
15.
16.
Amin V, Harris RA, Onuchic V, Jackson AR, Charnecki T, Paithankar S, et al. Epigenomic footprints across 111 reference epigenomes reveal tissue-specific epigenetic regulation of lincRNAs. Nat Commun. 2015;6:6370.PubMedCrossRef
17.
Wang Z, Yang B, Zhang M, Guo W, Wu Z, Wang Y, et al. lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer. Cancer Cell. 2018;33(4):706–20 e9.PubMedPubMedCentralCrossRef
18.
Lu C, Wei Y, Wang X, Zhang Z, Yin J, Li W, et al. DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma. Mol Cancer. 2020;19(1):28.PubMedPubMedCentralCrossRef
19.
Wang B, Zhao L, Chi W, Cao H, Cui W, Meng W. Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma. Epigenetics Chromatin. 2019;12(1):35.PubMedPubMedCentralCrossRef
20.
Xu H, Sun Y, Ma Z, Xu X, Qin L, Luo B. LOC134466 methylation promotes oncogenesis of endometrial carcinoma through LOC134466/hsa-miR-196a-5p/TAC1 axis. Aging. 2018;10(11):3353–70.PubMedPubMedCentralCrossRef
21.
Cheng G, Liu D, Liang H, Yang H, Chen K, Zhang X. A cluster of long non-coding RNAs exhibit diagnostic and prognostic values in renal cell carcinoma. Aging. 2019;11(21):9597–615.PubMedPubMedCentralCrossRef
22.
Kumegawa K, Maruyama R, Yamamoto E, Ashida M, Kitajima H, Tsuyada A, et al. A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer. Sci Rep. 2016;6:26699.PubMedPubMedCentralCrossRef
23.
Carlevaro-Fita J, Johnson R. Global positioning system: understanding long noncoding RNAs through subcellular localization. Mol Cell. 2019;73(5):869–83.PubMedCrossRef
24.
25.
Wang G, Zhang ZJ, Jian WG, Liu PH, Xue W, Wang TD, et al. Novel long noncoding RNA OTUD6B-AS1 indicates poor prognosis and inhibits clear cell renal cell carcinoma proliferation via the Wnt/β-catenin signaling pathway. Mol Cancer. 2019;18(1):15.PubMedPubMedCentralCrossRef
26.
Chen H, Shi Z, Guo J, Chang KJ, Chen Q, Yao CH, et al. The human mitochondrial 12S rRNA m(4)C methyltransferase METTL15 is required for mitochondrial function. J Biol Chem. 2020;295(25):8505–13.PubMedPubMedCentralCrossRef
27.
Singh RK, Saini SK, Prakasam G, Kalairasan P, Bamezai RNK. Role of ectopically expressed mtDNA encoded cytochrome c oxidase subunit I (MT-COI) in tumorigenesis. Mitochondrion. 2019;49:56–65.PubMedCrossRef
28.
Sulkshane P, Duek I, Ram J, Thakur A, Reis N, Ziv T, et al. Inhibition of proteasome reveals basal mitochondrial ubiquitination. J Proteome. 2020;229:103949.CrossRef
29.
30.
31.
Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15(1):7–21.PubMedCrossRef
32.
Yu AM, Ingelman-Sundberg M, Cherrington NJ, Aleksunes LM, Zanger UM, Xie W, et al. Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21(st) international symposium on Microsomes and drug oxidations (MDO). Acta Pharm Sin B. 2017;7(2):241–8.PubMedPubMedCentralCrossRef
33.
Joosten SC, Smits KM, Aarts MJ, Melotte V, Koch A, Tjan-Heijnen VC, et al. Epigenetics in renal cell cancer: mechanisms and clinical applications. Nat Rev Urol. 2018;15(7):430–51.PubMedCrossRef
34.
Lasseigne BN, Brooks JD. The role of DNA methylation in renal cell carcinoma. Mol Diagnosis Ther. 2018;22(4):431–42.CrossRef
35.
36.
Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 2018;46(D1):D303–d7.PubMedCrossRef
37.
Zhou KI, Parisien M, Dai Q, Liu N, Diatchenko L, Sachleben JR, et al. N(6)-Methyladenosine Modification in a Long Noncoding RNA Hairpin Predisposes Its Conformation to Protein Binding. J Mol Biol. 2016;428(5 Pt A):822–33.PubMedCrossRef
38.
Yang D, Qiao J, Wang G, Lan Y, Li G, Guo X, et al. N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. Nucleic Acids Res. 2018;46(8):3906–20.PubMedPubMedCentralCrossRef
39.
Yang X, Zhang S, He C, Xue P, Zhang L, He Z, et al. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer. 2020;19(1):46.PubMedPubMedCentralCrossRef
40.
Zuo X, Chen Z, Gao W, Zhang Y, Wang J, Wang J, et al. M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma. J Hematol Oncol. 2020;13(1):5.PubMedPubMedCentralCrossRef
41.
Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m(6)A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer cell. 2017;31(4):591–606 e6.PubMedPubMedCentralCrossRef
42.
Hu X, Peng WX, Zhou H, Jiang J, Zhou X, Huang D, et al. IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader. Cell Death Differ. 2020;27(6):1782–94.PubMedCrossRef
43.
Yi YC, Chen XY, Zhang J, Zhu JS. Novel insights into the interplay between m(6)a modification and noncoding RNAs in cancer. Mol Cancer. 2020;19(1):121.PubMedPubMedCentralCrossRef
44.
Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505(7481):117–20.PubMedCrossRef
45.
Cavalcante GC, Marinho ANR, Anaissi AK, Vinasco-Sandoval T, Ribeiro-Dos-Santos A, Vidal AF, et al. Whole mitochondrial genome sequencing highlights mitochondrial impact in gastric cancer. Sci Rep. 2019;9(1):15716.PubMedPubMedCentralCrossRef
46.
Ma H, Wang X, Cai J, Dai Q, Natchiar SK, Lv R, et al. N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat Chem Biol. 2019;15(1):88–94.PubMedCrossRef
47.
Kuo CL, Chou HY, Chiu YC, Cheng AN, Fan CC, Chang YN, et al. Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis. Cancer Lett. 2020;474:138–50.PubMedCrossRef
48.
Chandra D, Liu JW, Tang DG. Early mitochondrial activation and cytochrome c up-regulation during apoptosis. J Biol Chem. 2002;277(52):50842–54.PubMedCrossRef
49.
Chwa M, Atilano SR, Hertzog D, Zheng H, Langberg J, Kim DW, et al. Hypersensitive response to oxidative stress in keratoconus corneal fibroblasts. Invest Ophthalmol Vis Sci. 2008;49(10):4361–9.PubMedCrossRef
Metadata
Title
RETRACTED ARTICLE: Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1
Authors
Wuping Yang
Kenan Zhang
Lei Li
Yawei Xu
Kaifang Ma
Haibiao Xie
Jingcheng Zhou
Lin Cai
Yanqing Gong
Kan Gong
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-01889-8

Other articles of this Issue 1/2021

Journal of Experimental & Clinical Cancer Research 1/2021 Go to the issue

Research

Ex vivo expanded allogeneic natural killer cells have potent cytolytic activity against cancer cells through different receptor-ligand interactions

Correction

Correction to: Pyroptosis: a new paradigm of cell death for fighting against cancer

Research

HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression

Review

CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy

Research

Inhibiting the redox function of APE1 suppresses cervical cancer metastasis via disengagement of ZEB1 from E-cadherin in EMT

Research

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer
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