The occurence and development of tumors is a complicated process, which not only depends on the mutation or deletion of genes, but also is affected by epigenetic regulation. Accumulating evidences have shown that epigenetic modifications play fundamental roles in transcriptional regulation, heterochromatin formation, X chromosome inactivation, DNA damage response and tumor development. SET domain containing lysine methyltransferase 7 (SETD7) was initially identified as an important lysine methyltransferase, which methylated histone and non-histone proteins. These modifications play fundamental roles. Once this modification disorders, it can directly lead to cell abnormalities and cause many diseases. Studies have shown that SETD7 is related to the occurence and development of various tumors, but the methylation sites of SETD7 and its regulatory mechanism have not been fully elucidated. This article summarizes the research progress of the role of SETD7 on histone and non-histone methylation modification in tumors and the molecular mechanism, in order to provide new therapeutic targets for tumor pathogenesis and diagnosis.
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Humans ; Epigenesis, Genetic ; Histone-Lysine N-Methyltransferase/metabolism* ; Lysine/metabolism* ; Lung Neoplasms/genetics* ; Histones/metabolism*

OBJECTIVES: Our previous study has verified that high level of SET and MYND domain-containing protein 2 (SMYD2) plays an important role in acquiring aggressive ability for liver cancer cells in hepatocellular carcinoma. MiR-200b as a tumor suppressor gene involves in a variety of cancers. This study aims to investigate the correlation between miR-200b and SMYD2 in hepatocellular carcinoma and the underlying mechanism. METHODS: Firstly, the levels of SMYD2 and miR-200b in hepatocellular carcinoma tissues and matched adjacent non-tumor liver tissues were tested with real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Secondly, we evaluated the interaction between miR-200b and SMYD2 using dual-luciferase reporter assay. Thirdly, we elucidated the effect of miR-200b on SMYD2 and its downstream targets p53/CyclinE1. Finally, we silenced SMYD2 in hepatocellular carcinoma cell lines to investigate its effect on tumor proliferation and cell cycle progression, and further confirmed the correlation among SMYD2 and p53/CyclinE1. RESULTS: Compared with the matched adjacent non-tumor liver tissues, miR-200b was obviously decreased, and SMYD2 was significantly increased in hepatocellular carcinoma (both P<0.05). Spearman's rank correlation revealed that miR-200b expression was negatively correlated with SMYD2 (P<0.01). Computer algorithm and dual-luciferase reporter assay revealed that miR-200b directly targeted and suppressed SMYD2 in HEK 293T cells. The down-regulated miR-200b expression promoted hepatoma cell proliferation (P<0.05) and increased SMYD2 expression(P<0.01), while the up-regulated expression of miR-200b had an opposite effect. The knockdown of SMYD2 suppressed the proliferation of MHCC-97L cells (P<0.01), down-regulated CyclinE1, and up-regulated p53 expression (both P<0.05). CONCLUSIONS MiR-200b is involved in hepatocellular carcinoma progression via targeting SMYD2 and regulating SMYD2/p53/CyclinE1 signaling pathway and may be used as a potential target for hepatocellular carcinoma treatment.
Humans ; Carcinoma, Hepatocellular/pathology* ; Tumor Suppressor Protein p53/metabolism* ; MicroRNAs/metabolism* ; Cell Line, Tumor ; Signal Transduction ; Liver Neoplasms/pathology* ; Cell Proliferation/genetics* ; Histone-Lysine N-Methyltransferase/metabolism*

No abstract available.
Adult ; Antigens, CD4/*metabolism ; Antigens, CD56/*metabolism ; Bone Marrow/metabolism/pathology ; Dendritic Cells/cytology/*metabolism ; Diagnostic Errors ; Exons ; Female ; Flow Cytometry ; Gene Rearrangement ; Hematologic Neoplasms/diagnosis ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Leukemia, Myeloid, Acute/*diagnosis ; Male ; Middle Aged ; Myeloid-Lymphoid Leukemia Protein/genetics ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Transcription Factors/genetics ; Translocation, Genetic

No abstract available.
Base Sequence ; Cell Cycle Proteins/*genetics ; Chromosomes, Human, Pair 11 ; Chromosomes, Human, Pair 22 ; Female ; Gene Rearrangement ; Histone-Lysine N-Methyltransferase/*genetics ; Humans ; Immunophenotyping ; In Situ Hybridization, Fluorescence ; Karyotype ; Leukemia, Myeloid, Acute/*diagnosis/metabolism ; Male ; Myeloid-Lymphoid Leukemia Protein/*genetics ; Oncogene Proteins, Fusion/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Septins/*genetics ; Sequence Analysis, DNA ; Translocation, Genetic ; Young Adult

During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
Animals ; Breast Neoplasms ; genetics ; pathology ; physiopathology ; Cell Transformation, Neoplastic ; Chromatin ; genetics ; metabolism ; Epigenesis, Genetic ; physiology ; Epithelial Cells ; cytology ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Histone-Lysine N-Methyltransferase ; Humans ; Mammary Glands, Animal ; cytology ; growth & development ; Mammary Glands, Human ; cytology ; growth & development ; Myeloid-Lymphoid Leukemia Protein ; genetics ; physiology ; Polycomb-Group Proteins ; genetics ; physiology ; Receptors, Estrogen ; metabolism

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.
Acetylation/drug effects ; Adolescent ; Adult ; Aged ; Apoptosis/*drug effects ; Cadherins/metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p15/metabolism ; DNA Methylation/drug effects ; Enzyme Inhibitors/therapeutic use/*toxicity ; Frizzled Receptors/metabolism ; Gene Expression Regulation/drug effects ; HL-60 Cells ; Histone Deacetylase Inhibitors/therapeutic use/*toxicity ; Histone-Lysine N-Methyltransferase/*antagonists & inhibitors/metabolism ; Histones/genetics/metabolism ; Humans ; Hydroxamic Acids/therapeutic use/*toxicity ; K562 Cells ; Leukemia/drug therapy/metabolism/pathology ; Leukemia, Myeloid, Acute/genetics/metabolism/pathology ; Male ; Middle Aged ; Piperazines/therapeutic use/toxicity ; Promoter Regions, Genetic ; Young Adult

Histone lysine methyltransferase EZH2 has been reported to be frequently overexpressed in hepatocellular carcinoma (HCC) tissues and associated with hepatocarcinogenesis. However, the exact mechanism of EZH2 up-regulation in HCC has not been determined. In this study, we used murine hepatocyte AML12 cells to investigate the role of hepatitis B virus X protein (HBx) in regulating the expression of mEZH2. Western blot analysis demonstrated that the expression level of mEZH2 protein in AML12 cells was up-regulated by HBx in a dose-dependent manner. To further investigate the mechanism of mEZH2 overexpression, the 2500 bp regulatory sequence upstream from the first exon of the mEZH2 gene was amplified from AML12 genomic DNA and constructed into a luciferase reporter plasmid. The luciferase activity of the mEZH2 promoter significantly increased in AML12 cells co-transfected with HBx plasmid, and deleting the -486/-214 promoter region decreased HBx-induced mEZH2 promoter activation by nearly 50%. The -486/-214 region was then analyzed in the TRANSFAC 6.0 database and a typical E2F1-binding site was found. Mutation of this E2F1-binding site or knockdown of E2F1 expression by RNAi led to a dramatic decrease in HBx-induced activation of the mEZH2 promoter and mEZH2 overexpression in AML12 cells. These results provide evidence that HBx up-regulates mEZH2 expression by transactivating the mEZH2 promoter through E2F1 transcription factor, thereby providing new epigenetic evidence for the carcinogenic effect of HBx.
Animals ; Binding Sites ; Cell Line ; E2F1 Transcription Factor ; genetics ; Enhancer of Zeste Homolog 2 Protein ; Hepatocytes ; cytology ; metabolism ; virology ; Histone-Lysine N-Methyltransferase ; genetics ; metabolism ; Mice ; Plasmids ; Polycomb Repressive Complex 2 ; Promoter Regions, Genetic ; genetics ; RNA, Small Interfering ; genetics ; Trans-Activators ; genetics ; metabolism ; Transfection ; Up-Regulation

MLL1 is a histone H3Lys4 methyltransferase and forms a complex with WDR5 and other components. It plays important roles in developmental events, transcriptional regulation, and leukemogenesis. MLL1-fusion proteins resulting from chromosomal translocations are molecular hallmarks of a special type of leukemia, which occurs in over 70% infant leukemia patients and often accompanies poor prognosis. Investigations in the past years on leukemogenesis and the MLL1-WDR5 histone H3Lys4 methyltransferase complex demonstrate that epigenetic regulation is one of the key steps in development and human diseases.
Animals ; DNA Methylation ; Epigenesis, Genetic ; Histone-Lysine N-Methyltransferase ; genetics ; metabolism ; Histones ; metabolism ; Humans ; Leukemia ; genetics ; metabolism ; Lysine ; metabolism ; Multiprotein Complexes ; genetics ; metabolism ; Myeloid-Lymphoid Leukemia Protein ; genetics ; metabolism ; Transcriptional Activation

The translocation t(10;11)(p13;q14q21) has been found to be recurrent in acute lymphoblastic and myeloid leukemias, and results in the fusion of the clathrin assembly lymphoid myeloid leukemia (CALM) gene with the AF10 gene; these genes are present on chromosomes 11 and 10, respectively. Because the CALM-AF10 rearrangement is a rare chromosomal abnormality, it is not included in routine molecular tests for acute leukemia. Here, we describe the cases of 2 patients with the CALM-AF10 fusion gene. The first patient (case 1) was diagnosed with T-cell ALL, and the second patient (case 2) was diagnosed with AML. Both patient samples showed expression of the homeobox A gene cluster and the histone methyltransferase hDOT1L, which suggests that they mediate leukemic transformation in CALM-AF10-positive and mixed-lineage leukemia-AF10-positive leukemias. Both patients achieved complete remission after induction chemotherapy. The first patient (case 1) relapsed after double-unit cord blood transplantation; there was no evidence of relapse in the second patient (case 2) after allogenic peripheral blood stem cell transplantation. Since CALM-AF10- positive leukemias have been shown to have poor prognosis with conventional therapy, molecular tests for CALM-AF10 rearrangement would be necessary to detect minimal residual disease during follow-up.
Adolescent ; Adult ; Bone Marrow/pathology ; Chromosomes, Human, Pair 10 ; Chromosomes, Human, Pair 11 ; Cord Blood Stem Cell Transplantation ; Female ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Homeodomain Proteins/genetics/metabolism ; Humans ; Leukemia, Myeloid, Acute/diagnosis/*genetics/therapy ; Male ; Monomeric Clathrin Assembly Proteins/*genetics ; Oncogene Proteins, Fusion/*genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/*genetics/therapy ; Recurrence ; Transcription Factors/*genetics ; Translocation, Genetic

OBJECTIVETo explore the role SMYD3 and histone methylation in the carcinogenesis of HBV-related hepatocellular carcinoma (HCC).

METHODSHBx expressing plasmid was transfected into HepG2 cell, the localization of HBx and SMYD3 was detected by immunofluorescence, SMYD3 mRNA and protein were checked by real-time reverse transcription polymerase chain reaction and western blot, cell proliferation and apoptosis were detected by flow cytometry.

RESULTSAfter HBx transfection, HBx and SMYD3 protein were mainly localized in nucleus. HBx protein enhanced SMYD3 mRNA and SMYD3 expressions in HepG2. After HBx transfection, apoptosis of HepG2 was decreased, and cell proliferation was increased.

CONCLUSIONSHBx may induce the expression of histone methyltransferase SMYD3, which in turn stimulates cell proliferation and blocks apoptosis.

Apoptosis ; Blotting, Western ; Carcinoma, Hepatocellular ; genetics ; metabolism ; pathology ; Cell Proliferation ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; Hep G2 Cells ; Hepatitis B virus ; genetics ; Histone-Lysine N-Methyltransferase ; genetics ; metabolism ; Humans ; Liver Neoplasms ; genetics ; metabolism ; pathology ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Trans-Activators ; genetics ; metabolism ; Transfection ; Up-Regulation