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      The RNA methyltransferase NSUN6 suppresses pancreatic cancer development by regulating cell proliferation

      research-article
      Author(s): a , 1 , b , 1 , c , 1 , a , 1 , c , d , d , c , c , * , a , c , **
      Publication date (Electronic):
      Journal: EBioMedicine
      Publisher: Elsevier
      Keywords: Pancreatic cancer, 5-methylcytosine, NSUN6, Cell proliferation, PC, pancreatic cancer, m5C, 5-methylcytosine, GEO, Gene Expression Omnibus, NSUN6, NOP2/Sun domain family, member 6, FFPE, formalin-fixed paraffin-embedded, OS, overall survival, TCGA, The Cancer Genome Atlas, GSEA, gene set enrichment analysis, NES, normalized enrichment scores, FDR, false discovery rate, qPCR, quantitative PCR, IHC, immunohistochemical, SEM, standard error of mean, ROC, receiver operating characteristics curve, AUC, area under the curve, HR, Hazard ratios, CI, confidence interval, KPC, KrasG12D/+&Trp53R172H/+&Pdx1-Cre, PanIN, pancreatic intraepithelial neoplasia, DFS, disease free survival, KEGG, Kyoto Encyclopaedia of Genes and Genomes, CGN, Cancer Gene Neighborhoods, GO, gene ontology, CDK, cyclin-dependent kinase, CDKN, cyclin-dependent kinase inhibitor, m6A, N6-methyladenosine, NSUN, NOL1/NOP2/SUN domain

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          Abstract

          Background

          Pancreatic cancer (PC) is one of the most lethal solid malignancies in the world due to its excessive cell proliferation and aggressive metastatic features. Emerging evidences revealed the importance of posttranscriptional modifications of RNAs in PC progression. However, knowledge about the 5-methylcytosine (m5C) RNA modification in PC is still extremely limited. In this study, we attempted to explore the expression changes and clinical significances of 12 known m5C-related genes among PC patients.

          Methods

          A total of 362 normal and 382 tumor specimens from PC patients were examined for candidate m5C-related gene and protein expression by using quantitative PCR (qPCR) and immunohistochemistry (IHC). The proliferation rate of PC cells was detected by MTS assay. Xenograft mouse models were used to assess the role of NSUN6 in PC tumor formation.

          Findings

          Through analyzing the four Gene Expression Omnibus (GEO) databases, six m5C-related genes shown significant and consistent alterations were selected for further examination in our 3 independent PC cohorts. Finally, we identified the reduction of NSUN6 as a common feature of all PC sample sets examined. NSUN6 expression correlated with clinicopathologic parameters including T stage, and Ki67 + cell rate. Further assessing the transcriptional profiles of 50 PC tissues, we found biological processes associated with cell proliferation like cell cycle and G2M checkpoint were enriched in NSUN6 lower expression group. Helped by in vitro PC cell lines and in vivo xenograft mouse models, we confirmed the role of NSUN6 in regulating cell proliferation and PC tumor growth. Last but also importantly, we also show the good performance of NSUN6 in evaluating tumor recurrence and survival among PC patients.

          Interpretation

          Our data suggested that NSUN6 is an important factor involved in regulating cell proliferation of PC, and highlights the potential of novel m5C-based clinical modalities as a therapeutic approach in PC patients.

          Funding

          This study was supported by the National Natural Science Foundation of China (Grant Nos. 81803014, 81802424, and 81802911).

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          Most cited references39

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          Dynamic RNA Modifications in Gene Expression Regulation

          Molly E Evans, Ian A Roundtree, Tao Pan … (2017)
          Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.
          Article 0 comments Cited 1091 times – based on 0 reviews     Review now
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            The role of m 6 A RNA methylation in human cancer

            Xiao-Yu Chen, Jing Zhang, Jin-Shui Zhu (2019)
            N6-methyladenosine (m6A) is identified as the most common, abundant and conserved internal transcriptional modification, especially within eukaryotic messenger RNAs (mRNAs). M6A modification is installed by the m6A methyltransferases (METTL3/14, WTAP, RBM15/15B and KIAA1429, termed as “writers”), reverted by the demethylases (FTO and ALKBH5, termed as “erasers”) and recognized by m6A binding proteins (YTHDF1/2/3, IGF2BP1 and HNRNPA2B1, termed as “readers”). Acumulating evidence shows that, m6A RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers. Until now, the molecular mechanisms underlying m6A RNA methylation in various tumors have not been comprehensively clarified. In this review, we mainly summarize the recent advances in biological function of m6A modifications in human cancer and discuss the potential therapeutic strategies.
            Article 0 comments Cited 508 times – based on 0 reviews     Review now
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              Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.

              Sunil R Hingorani, Lifu Wang, Asha Multani … (2005)
              To define the genetic requirements for pancreatic ductal adenocarcinoma (PDA), we have targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas, revealing the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease. The primary carcinomas and metastases demonstrate a high degree of genomic instability manifested by nonreciprocal translocations without obvious telomere erosion-hallmarks of human carcinomas not typically observed in mice. No mutations were discovered in other cardinal tumor suppressor gene pathways, which, together with previous results, suggests that there are distinct genetic pathways to PDA with different biological behaviors. These findings have clear implications for understanding mechanisms of disease pathogenesis, and for the development of detection and targeted treatment strategies.
              Article 0 comments Cited 466 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Linhua Yang
                Ming Zhan
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 06 January 2021
                Publication date Collection: January 2021
                Publication date (Electronic): 06 January 2021
                Volume: 63
                Electronic Location Identifier: 103195
                Affiliations
                [a ]The Core Laboratory in Medical Centre of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
                [b ]Department of Pancreatic-biliary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
                [c ]Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
                [d ]Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
                Author notes
                [* ]Corresponding author. yanglinhua1981@ 123456126.com
                [** ]Corresponding author at: The Core Laboratory in Medical Centre of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China. zhanming@ 123456shsmu.edu.cn
                [1]

                These authors contributed equally.

                Article
                Publisher Item ID: S2352-3964(20)30571-5 Publisher ID: 103195
                DOI: 10.1016/j.ebiom.2020.103195
                PMC ID: 7804980
                PubMed ID: 33418496
                SO-VID: 44b3ebb2-d9d3-45e3-9299-d3a052886186
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 12 October 2020
                Date revision received : 3 December 2020
                Date accepted : 15 December 2020
                Categories
                Subject: Research Paper

                Keywords: pancreatic cancer,5-methylcytosine,nsun6,cell proliferation,pc, pancreatic cancer,m5c, 5-methylcytosine,geo, gene expression omnibus,nsun6, nop2/sun domain family, member 6,ffpe, formalin-fixed paraffin-embedded,os, overall survival,tcga, the cancer genome atlas,gsea, gene set enrichment analysis,nes, normalized enrichment scores,fdr, false discovery rate,qpcr, quantitative pcr,ihc, immunohistochemical,sem, standard error of mean,roc, receiver operating characteristics curve,auc, area under the curve,hr, hazard ratios,ci, confidence interval,kpc, krasg12d/+&trp53r172h/+&pdx1-cre,panin, pancreatic intraepithelial neoplasia,dfs, disease free survival,kegg, kyoto encyclopaedia of genes and genomes,cgn, cancer gene neighborhoods,go, gene ontology,cdk, cyclin-dependent kinase,cdkn, cyclin-dependent kinase inhibitor,m6a, n6-methyladenosine,nsun, nol1/nop2/sun domain
                Data availability:
                Keywords: pancreatic cancer, 5-methylcytosine, nsun6, cell proliferation, pc, pancreatic cancer, m5c, 5-methylcytosine, geo, gene expression omnibus, nsun6, nop2/sun domain family, member 6, ffpe, formalin-fixed paraffin-embedded, os, overall survival, tcga, the cancer genome atlas, gsea, gene set enrichment analysis, nes, normalized enrichment scores, fdr, false discovery rate, qpcr, quantitative pcr, ihc, immunohistochemical, sem, standard error of mean, roc, receiver operating characteristics curve, auc, area under the curve, hr, hazard ratios, ci, confidence interval, kpc, krasg12d/+&trp53r172h/+&pdx1-cre, panin, pancreatic intraepithelial neoplasia, dfs, disease free survival, kegg, kyoto encyclopaedia of genes and genomes, cgn, cancer gene neighborhoods, go, gene ontology, cdk, cyclin-dependent kinase, cdkn, cyclin-dependent kinase inhibitor, m6a, n6-methyladenosine, nsun, nol1/nop2/sun domain

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