摘要
背景:MBD1(甲基化CpG结合域蛋白1)在胰腺癌中高度表达。Nrf2(NF-E2 p45相关因子2)和“抗氧化反应元件”是驱动的基因,Nrf2控制经常上调胰腺癌预后差相关。KEAP1(Kelch-like ECH-associated protein 1)是一种显性负调节Nrf2和报道是通过启动子甲基化的表观遗传调控。然而,与抗氧化反应和关联作用Keap1 MBD1未曾报道,尚不清楚。 目的:研究在胰腺癌细胞KEAP1转录抗氧化反应及其调节功能MBD1的作用。 方法:MBD1来研究其抗氧化反应中的作用结果是失效的。为了探索潜在的机制,转录和KEAP1蛋白水平已被检测。MBD1和KEAP1之间的相关性,采用免疫组织化学证实在胰腺癌组织样本(IHC)。双荧光素酶报告实验和染色质免疫沉淀(ChIP)被用来阐明机制和 MBD1基因的转录调控。此外,免疫共沉淀(CoIP)进行检测,发现在转录调控通过Keap1 MBD1与c-myc作用的关系。 结果:MBD1的失活降低抗氧化反应和相关的靶基因,通过Keap1的表观遗传调控。MBD1与胰腺癌组织标本KEAP1呈负相关。此外,c-myc与MBD1相互作用。 结论:MBD1可通过 KEAP1下调诱导抗氧化反应胰腺癌。c-myc基因在MBD1介导失活KEAP1的表观遗传起着关键的作用。
关键词: 胰腺癌,MBD1,抗氧化反应,KEAP1,NRF2,c-myc,基因的表观遗传调控。
Current Molecular Medicine
Title:MBD1 is an Epigenetic Regulator of KEAP1 in Pancreatic Cancer
Volume: 16 Issue: 4
Author(s): B. Zhang, J. Xu, C. Li, S. Shi, S. Ji, W. Xu, J. Liu, K. Jin, D. Liang, C. Liang, L. Liu, C. Liu, Y. Qin, X. Yu
Affiliation:
关键词: 胰腺癌,MBD1,抗氧化反应,KEAP1,NRF2,c-myc,基因的表观遗传调控。
摘要: Background: MBD1 (Methyl-CpG Binding Domain Protein 1) is highly expressed in pancreatic cancer. Nrf2 (NF-E2 p45-related factor 2) and the ‘antioxidant response element’ (ARE)-driven genes that NRF2 controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Keap1 (Kelch-like ECH-associated protein 1) is a dominant negative regulator of NRF2 and is reported to be epigenetically regulated by promoter methylation. However, the role of MBD1 with antioxidant response and its association with KEAP1 has never been reported before and remains unclear.
Objective: We investigated the role of MBD1 in antioxidant response and its regulatory function in KEAP1 transcription in pancreatic cancer cells.
Method: MBD1 was silenced to examine its role in antioxidant response. To explore the underlying mechanism, transcriptional and protein levels of KEAP1 was examined. The correlation between MBD1 and KEAP1 was confirmed in pancreatic cancer tissue samples by using immunohistochemistry (IHC). Dualluciferase reporter assay and Chromatin immunoprecipitation (ChIP) were used to elucidate he mechanism of MBD1 in KEAP1 transcriptional control. Moreover, co-immunoprecipitation (CoIP) assay was performed to uncover the regulatory role of MBD1 in KEAP1 transcription through its association with c-myc.
Results: MBD1 silencing decreased antioxidant response and the related ARE target genes through epigenetic regulation of KEAP1. MBD1 negatively correlated with KEAP1 in pancreatic cancer tissue samples. Moreover, c-myc was a MBD1 interaction partner in KEAP1 epigenetic regulation.
Conclusion: MBD1 can induce antioxidant response in pancreatic cancer through down-regulation of KEAP1. c-myc plays a key role in MBD1 mediated epigenetic silencing of KEAP1.
Export Options
About this article
Cite this article as:
B. Zhang, J. Xu, C. Li, S. Shi, S. Ji, W. Xu, J. Liu, K. Jin, D. Liang, C. Liang, L. Liu, C. Liu, Y. Qin, X. Yu , MBD1 is an Epigenetic Regulator of KEAP1 in Pancreatic Cancer, Current Molecular Medicine 2016; 16 (4) . https://dx.doi.org/10.2174/1566524016666160316154150
DOI https://dx.doi.org/10.2174/1566524016666160316154150 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Withdrawal Notice: Drug Repurposing for Prospective Anti-Cancer Agents Along with the Clinical Status of the Repurposed Drug
Anti-Cancer Agents in Medicinal Chemistry The Use of Fas Ligand, TRAIL and Bax in Gene Therapy of Prostate Cancer
Current Gene Therapy New Framework for the Discovery of PRC2 Inhibitors: Epigenetic Drugs
Current Drug Targets Expanding Spectrum of Sodium Potassium Chloride Co-transporters in the Pathophysiology of Diseases
Current Neuropharmacology A Discussion Regarding the Application of the Hertz Contact Theory on Biological Samples in AFM Nanoindentation Experiments
Micro and Nanosystems Anticancer Natural Products with Collateral Sensitivity: A Review
Mini-Reviews in Medicinal Chemistry Editorial (Hot Topic: Translational Medicine is Promoting Cross-talk of Interdiscipline)
Anti-Cancer Agents in Medicinal Chemistry Targeting Angiogenesis for Treatment of NSCLC Brain Metastases
Current Cancer Drug Targets Monitoring Cell Therapy Using Iron Oxide MR Contrast Agents
Current Pharmaceutical Biotechnology P2Y Receptors: Focus on Structural, Pharmacological and Functional Aspects in the Brain
Current Medicinal Chemistry Editorial [Hot Topic: ADAMs: Targets for Drug Discovery (Executive Editor: Marcia L. Moss)]
Current Pharmaceutical Design Adaptor Protein 3BP2 and Cherubism
Current Medicinal Chemistry Curcumin in Combined Cancer Therapy
Current Pharmaceutical Design Prediction and Early Evaluation of Anticancer Therapy Response: From Imaging of Drug Efflux Pumps to Targeted Therapy Response
Current Medicinal Chemistry Opioid Receptor Interacting Proteins and the Control of Opioid Signaling
Current Pharmaceutical Design Sirtuin Modulators: Mechanisms and Potential Clinical Implications
Current Medicinal Chemistry Application of Targeted Therapy to Malignant Gliomas and Response to Treatment
Current Signal Transduction Therapy Molecular Mechanisms Regulating mRNA Stability: Physiological and Pathological Significance
Current Genomics Modulation of Photosensitization Processes for an Improved Targeted Photodynamic Therapy
Current Medicinal Chemistry A Combination of Two Antioxidants (An SOD Mimic and Ascorbate) Produces a Pro-Oxidative Effect Forcing Escherichia coli to Adapt Via Induction of oxyR Regulon
Anti-Cancer Agents in Medicinal Chemistry