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DNMT1 and EZH2 mediated methylation silences the microRNA-200b/a/429 gene and promotes tumor progression.

Abstract Aberrant expression of the microRNA-200 (miR-200) family has been linked to the occurrence and development of various types of malignant tumors, including hepatocellular carcinoma (HCC), colon cancer and breast cancer. However, little is known about the precise mechanism by which miR-200 expression is downregulated. The intricate relationship between DNA methylation and histone modifications has become a subject of increasing interest. The expression of miR-200 family members is modified by similar or complementary epigenetic mechanisms in MGC-803 and BGC-823 gastric cancer cells and U87 MG glioma cells. Chromatin immunoprecipitation assays revealed that DNA methyltransferase 1 (DNMT1) bound to miR-200b/a/429 promoter regions, indicating an interaction between DNMT1 and the miR-200b/a/429 promoter. Furthermore, Co-Immunoprecipitation (Co-IP) detection showed that DNMT1, together with the PcG protein Enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase, contributed to the transcriptional repression of microRNA-200 family members. Knockdown of EZH2 not only impacted H3K27 trimethylation but also reduced DNMT1 presence on the miR-200b/a/429 promoter. EZH2 appeared to be essential for DNMT1 recruitment to the promoter region. Silencing EZH2 and DNMT1 using drugs or RNA interference dramatically reduced the levels of miR-200b/a/429 expression. Collectively, these results indicated that EZH2 and DNMT1-mediated epigenetic silencing contributed to the progression of gastric cancer and glioblastoma, and therefore represents a novel therapeutic target for malignant tumors.
PMID
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Authors

Mayor MeshTerms
Keywords

DNA methylation

DNMT

EZH2

Histone modifications

miR-200

Journal Title cancer letters
Publication Year Start




PMID- 25595591
OWN - NLM
STAT- MEDLINE
DCOM- 20150420
LR  - 20171116
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 359
IP  - 2
DP  - 2015 Apr 10
TI  - DNMT1 and EZH2 mediated methylation silences the microRNA-200b/a/429 gene and
      promotes tumor progression.
PG  - 198-205
LID - 10.1016/j.canlet.2015.01.005 [doi]
LID - S0304-3835(15)00026-9 [pii]
AB  - Aberrant expression of the microRNA-200 (miR-200) family has been linked to the
      occurrence and development of various types of malignant tumors, including
      hepatocellular carcinoma (HCC), colon cancer and breast cancer. However, little
      is known about the precise mechanism by which miR-200 expression is
      downregulated. The intricate relationship between DNA methylation and histone
      modifications has become a subject of increasing interest. The expression of
      miR-200 family members is modified by similar or complementary epigenetic
      mechanisms in MGC-803 and BGC-823 gastric cancer cells and U87 MG glioma cells.
      Chromatin immunoprecipitation assays revealed that DNA methyltransferase 1
      (DNMT1) bound to miR-200b/a/429 promoter regions, indicating an interaction
      between DNMT1 and the miR-200b/a/429 promoter. Furthermore,
      Co-Immunoprecipitation (Co-IP) detection showed that DNMT1, together with the PcG
      protein Enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase,
      contributed to the transcriptional repression of microRNA-200 family members.
      Knockdown of EZH2 not only impacted H3K27 trimethylation but also reduced DNMT1
      presence on the miR-200b/a/429 promoter. EZH2 appeared to be essential for DNMT1 
      recruitment to the promoter region. Silencing EZH2 and DNMT1 using drugs or RNA
      interference dramatically reduced the levels of miR-200b/a/429 expression.
      Collectively, these results indicated that EZH2 and DNMT1-mediated epigenetic
      silencing contributed to the progression of gastric cancer and glioblastoma, and 
      therefore represents a novel therapeutic target for malignant tumors.
CI  - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved.
FAU - Ning, Xianghong
AU  - Ning X
AD  - Department of Gastroenterology, Tianjin Medical University General Hospital,
      Tianjin, China.
FAU - Shi, Zhendong
AU  - Shi Z
AD  - Department of Neurosurgery, Tianjin Medical University General Hospital, 154
      An-Shan Road, Heping District, Tianjin 300052, China; The 3rd Department of
      Breast Cancer Prevention, Treatment and Research Center, National Clinical
      Research Center of Cancer, Tianjin Medical University Cancer Institute and
      Hospital, Tianjin, China; Laboratory of Neuro-Oncology, Tianjin Neurological
      Institute, Tianjin, China; Key Laboratory of Post-trauma Neuro-repair and
      Regeneration in Central Nervous System, Ministry of Education, Tianjin, China;
      Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous
      System, Tianjin, China.
FAU - Liu, Xi
AU  - Liu X
AD  - Department of Gastroenterology, Tianjin Medical University General Hospital,
      Tianjin, China.
FAU - Zhang, Anling
AU  - Zhang A
AD  - Department of Neurosurgery, Tianjin Medical University General Hospital, 154
      An-Shan Road, Heping District, Tianjin 300052, China; Laboratory of
      Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of
      Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of 
      Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and
      Regeneration of Nervous System, Tianjin, China.
FAU - Han, Lei
AU  - Han L
AD  - Department of Neurosurgery, Tianjin Medical University General Hospital, 154
      An-Shan Road, Heping District, Tianjin 300052, China; Laboratory of
      Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of
      Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of 
      Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and
      Regeneration of Nervous System, Tianjin, China.
FAU - Jiang, Kui
AU  - Jiang K
AD  - Department of Gastroenterology, Tianjin Medical University General Hospital,
      Tianjin, China.
FAU - Kang, Chunsheng
AU  - Kang C
AD  - Department of Neurosurgery, Tianjin Medical University General Hospital, 154
      An-Shan Road, Heping District, Tianjin 300052, China; Laboratory of
      Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China; Key Laboratory of
      Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of 
      Education, Tianjin, China; Tianjin Key Laboratory of Injuries, Variations and
      Regeneration of Nervous System, Tianjin, China; Chinese Glioma Cooperative Group 
      (CGCG), 6 Tiantanxi Li, Beijing, China. Electronic address: [email protected]
FAU - Zhang, Qingyu
AU  - Zhang Q
AD  - Department of Gastroenterology, Tianjin Medical University General Hospital,
      Tianjin, China. Electronic address: [email protected]
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150113
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Histones)
RN  - 0 (MIRN200 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 544SH4020S (3-deazaneplanocin)
RN  - 776B62CQ27 (decitabine)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNMT1 protein, human)
RN  - EC 2.1.1.37 (Dnmt1 protein, mouse)
RN  - EC 2.1.1.43 (EZH2 protein, human)
RN  - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
RN  - EC 2.1.1.43 (Polycomb Repressive Complex 2)
RN  - K72T3FS567 (Adenosine)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Adenosine/analogs & derivatives/pharmacology
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Azacitidine/analogs & derivatives/pharmacology
MH  - Cell Line, Tumor
MH  - DNA (Cytosine-5-)-Methyltransferase 1
MH  - DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors/*physiology
MH  - DNA Methylation
MH  - Disease Progression
MH  - Enhancer of Zeste Homolog 2 Protein
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Silencing
MH  - Glioblastoma/therapy
MH  - Histones/metabolism
MH  - Humans
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - MicroRNAs/*genetics/metabolism
MH  - Polycomb Repressive Complex 2/antagonists & inhibitors/*physiology
MH  - Stomach Neoplasms/therapy
MH  - Tumor Burden
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - DNA methylation
OT  - DNMT
OT  - EZH2
OT  - Histone modifications
OT  - miR-200
EDAT- 2015/01/18 06:00
MHDA- 2015/04/22 06:00
CRDT- 2015/01/18 06:00
PHST- 2014/09/29 00:00 [received]
PHST- 2014/12/12 00:00 [revised]
PHST- 2015/01/08 00:00 [accepted]
PHST- 2015/01/18 06:00 [entrez]
PHST- 2015/01/18 06:00 [pubmed]
PHST- 2015/04/22 06:00 [medline]
AID - S0304-3835(15)00026-9 [pii]
AID - 10.1016/j.canlet.2015.01.005 [doi]
PST - ppublish
SO  - Cancer Lett. 2015 Apr 10;359(2):198-205. doi: 10.1016/j.canlet.2015.01.005. Epub 
      2015 Jan 13.