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      • Record: found
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      DNMT3a promotes proliferation by activating the STAT3 signaling pathway and depressing apoptosis in pancreatic cancer

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          Abstract

          Background

          Although aberrant DNA methyltransferase 3a (DNMT3a) expression is important to the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC), the role of DNMT3a in PDAC prognosis is not clarified yet due to the limited studies and lacking of underlying molecular mechanism.

          Methods

          The expression of DNMT3a was examined by immunohistochemistry in PDAC tissues. Gene expression profiles assays were conducted to explore the impact of DNMT3a on biological processes and signal pathways. Cell cycle and apoptosis were measured by flow cytometry. Western blotting and real-time qPCR assays were used to explore the impact of DNMT3a on expression of protein and mRNA related to cell cycle, STAT3 signaling pathway and apoptosis.

          Results

          DNMT3a was overexpressed and closely associated with poor outcomes of PDAC. DNMT3a knockdown restrained PDAC cell proliferation, induced cell cycle arrest and promoted apoptosis in vitro. Affymetrix GeneChip Human Transcriptome Array identified that the cell cycle-related process was most significantly associated with DNMT3a. DNMT3a knockdown induced G1-S phase transition arrest by decreasing the expression of cyclin D1, which was mediated by the reduction of IL8 and the subsequent inactivation of STAT3 signaling pathway. Furthermore, exogenous apoptosis was also promoted after DNMT3a knockdown, probably via up-regulation of DNA transcription and expression in CASP8.

          Conclusion

          These findings indicate that DNMT3a plays an important role in PDAC progression. DNMT3a may serve as a prognostic biomarker and a therapeutic strategy candidate in PDAC.

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          Most cited references38

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          DNA methylation, methyltransferases, and cancer.

          K D Robertson (2001)
          The field of epigenetics has recently moved to the forefront of studies relating to diverse processes such as transcriptional regulation, chromatin structure, genome integrity, and tumorigenesis. Recent work has revealed how DNA methylation and chromatin structure are linked at the molecular level and how methylation anomalies play a direct causal role in tumorigenesis and genetic disease. Much new information has also come to light regarding the cellular methylation machinery, known as the DNA methyltransferases, in terms of their roles in mammalian development and the types of proteins they are known to interact with. This information has forced a new view for the role of DNA methyltransferases. Rather than enzymes that act in isolation to copy methylation patterns after replication, the types of interactions discovered thus far indicate that DNA methyltransferases may be components of larger complexes actively involved in transcriptional control and chromatin structure modulation. These new findings will likely enhance our understanding of the myriad roles of DNA methylation in disease as well as point the way to novel therapies to prevent or repair these defects.
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            SOCS proteins: negative regulators of cytokine signaling.

            D. Krebs, D. Hilton (2001)
            Cytokines regulate the growth and differentiation of cells by binding to cell-surface receptors and activating intracellular signal transduction cascades such as the JAK-STAT pathway. Cytokine signaling is negatively regulated with respect to both magnitude and duration, and it is now clear that the suppressor of cytokine signaling (SOCS) family of proteins (SOCS1-SOCS7 and CIS) contributes significantly to this process. Transcripts encoding CIS, SOCS1, SOCS2, and SOCS3 are upregulated in response to cytokine stimulation, and the corresponding SOCS proteins inhibit cytokine-induced signaling pathways. SOCS proteins therefore form part of a classical negative feedback circuit. SOCS family members modulate signaling by several mechanisms, which include inactivation of the Janus kinases (JAKs), blocking access of the signal transducers and activators of transcription (STATs) to receptor binding sites, and ubiquitination of signaling proteins and their subsequent targeting to the proteasome. Gene targeting has been used to generate mice lacking socs1, socs2, or socs3, in order to elucidate the physiological function of these SOCS family members. The analysis of socs1(-/-) mice has revealed that SOCS1 plays a key role in the negative regulation of interferon-gamma signaling and in T cell differentiation. Socs2(-/-) mice are 30%-40% larger than wild-type mice, demonstrating that SOCS2 is a critical regulator of postnatal growth. Additionally, the study of embryos lacking socs3 has revealed that SOCS3 is an important regulator of fetal liver hematopoiesis. The biological role of other SOCS proteins remains to be determined.
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              Signaling through the JAK/STAT pathway, recent advances and future challenges.

              Marc Braunstein, T Kisseleva, S. Bhattacharya … (2002)
              Investigation into the mechanism of cytokine signaling led to the discovery of the JAK/STAT pathway. Following the binding of cytokines to their cognate receptor, signal transducers and activators of transcription (STATs) are activated by members of the janus activated kinase (JAK) family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. During the past several years significant progress has been made in the characterization of the JAK/STAT signaling cascade, including the identification of multiple STATs and regulatory proteins. Seven STATs have been identified in mammals. The vital role these STATs play in the biological response to cytokines has been demonstrated through the generation of murine 'knockout' models. These mice will be invaluable in carefully elucidating the role STATs play in regulating the host response to various stresses. Similarly, the solution of the crystal structure of two STATs has and will continue to facilitate our understanding of how STATs function. This review will highlight these exciting developments in JAK/STAT signaling.
              Article 0 comments Cited 142 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Manag Res
                Journal ID (iso-abbrev): Cancer Manag Res
                Journal ID (publisher-id): CMAR
                Journal ID (pmc): cancmanres
                Title: Cancer Management and Research
                Publisher: Dove
                ISSN (Electronic): 1179-1322
                Publication date (Electronic): 10 July 2019
                Publication date Collection: 2019
                Volume: 11
                Pages: 6379-6396
                Affiliations
                [1 ] The First Department of Oncology, Shengjing Hospital of China Medical University , Shenyang, People’s Republic of China
                [2 ] Department of Medical Oncology, The First Hospital of China Medical University , Shenyang, People’s Republic of China
                [3 ] Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University , Shenyang, People’s Republic of China
                [4 ] Department of Pathology, Shengjing Hospital of China Medical University , Shenyang, People’s Republic of China
                Author notes
                Correspondence: Xiang-Hong Yang Department of Pathology, Shengjing Hospital of China Medical University , No. 36, Sanhao Street, Heping District, Shenyang110004, People’s Republic of ChinaTel +86 24 966 157 5212Fax +86 242 389 2617 Email xhyang4933@ 123456vip.sina.com
                Xiao-Fang CheDepartment of Medical Oncology, The First Hospital of China Medical University , No. 155, North Nanjing Street, Heping District, Shenyang110001, People’s Republic of ChinaTel +86 248 328 2312Fax +86 248 328 2543Email xfche@ 123456cmu.edu.cn
                Article
                Publisher ID: 201610
                DOI: 10.2147/CMAR.S201610
                PMC ID: 6635825
                PubMed ID: 31372043
                SO-VID: d67c5cc4-1e3a-48c3-9dc1-209ad6ad915d
                Copyright © © 2019 Jing et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 15 January 2019
                Date accepted : 09 May 2019
                Page count
                Figures: 5, Tables: 3, References: 47, Pages: 18
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: dna methyltransferase 3a,pancreatic ductal adenocarcinoma,prognosis,proliferation
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: dna methyltransferase 3a, pancreatic ductal adenocarcinoma, prognosis, proliferation

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