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*

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.
DNA Methylation/*physiology ; Epigenesis, Genetic/*physiology ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/*metabolism ; Humans ; Models, Biological ; Neoplasms/*genetics

DNA methylation, histone modifications, and the chromatin structure are profoundly altered in human cancers. The silencing of cancer-related genes by these epigenetic regulators is recognized as a key mechanism in tumor formation. Recent findings revealed that DNA methylation and histone modifications appear to be linked to each other. However, it is not clearly understood how the formation of histone modifications may affect DNA methylation and which genes are relevantly involved with tumor formation. The presence of histone modifications does not always link to DNA methylation in human cancers, which suggests that another factor is required to connect these two epigenetic mechanisms. In this review, examples of studies that demonstrated the relationship between histone modifications and DNA methylation in human cancers are presented and the potential implications of these epigenetic mechanisms in human neoplasia are discussed.
DNA Methylation/*physiology ; Epigenesis, Genetic/*physiology ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/*metabolism ; Humans ; Models, Biological ; Neoplasms/*genetics

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*

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

OBJECTIVETo construct the eukaryotic expression plasmid of mouse histone lysine methyltransferase Setd7 and detect its effect on neuron development.

METHODSThe clone of mouse Setd7 was obtained and inserted into the eukaryotic expression vector pCMV-3tag-6-Flag. The plasmid was transfected into HEK 293T and identified by Western blot. Real-time PCR was used to detect the effect of Setd7 on the neuron differentiation marker gene Ngn 1 mRNA expression. Dual luciferase reporter system was used to detect the effect of Setd7 on Ngn 1 mRNA expression. Real-time PCR was used to detect the effect of Setd 7 siRNA plasmid on Ngn 1 mRNA expression.

RESULTSAn eukaryotic expression plasmid of Setd 7 was successfully constructed. Setd7 induced Ngn 1 mRNA expression and increased Ngn 1 promoter activity. Also, the knockdown of Setd 7 inhibited Ngn 1 mRNA expression.

CONCLUSIONHistone lysine methyltransferase Setd7 can enhance neuron differentiation marker gene Ngn 1 transcription.

Animals ; Basic Helix-Loop-Helix Transcription Factors ; genetics ; metabolism ; Gene Expression Regulation ; Genetic Vectors ; HEK293 Cells ; Histone-Lysine N-Methyltransferase ; genetics ; metabolism ; Humans ; Mice ; Nerve Tissue Proteins ; genetics ; metabolism ; Protein Methyltransferases ; genetics ; metabolism ; RNA, Messenger ; genetics ; Transfection

In multiple types of acute leukemia,a portion of the MLL protein is fused to a variety of other unrelated proteins. The activity of leukemic MLL fusions is believed to be directly contributing to the conversion of normal bone marrow cells into leukemic cancer cells. However, the mechanism of this process has not been fully elucidated. We have recently found that the MLL leukemic fusions can abolish the activity of P53 tumor suppressor protein that actively guards against the appearance of cancer by instructing damaged cells to self-destruct. In contrast to the vast majority of cancers where p53 gene is mutated, very few p53 mutations have been found in leukemias. Our findings suggest that leukemic fusions contribute to disease progression, at least in part, by suppressing the function of P53, which,if proven,may present a novel opportunity to re-activating the P53 pathway in leukemic cells thereby identifying a rational therapeutic approach for managing leukemias where MLL fusions are detected.
Chromosomes, Human, Pair 11 ; genetics ; Histone-Lysine N-Methyltransferase ; Humans ; Leukemia ; etiology ; genetics ; Myeloid-Lymphoid Leukemia Protein ; genetics ; metabolism ; physiology ; Oncogene Proteins, Fusion ; metabolism ; physiology ; Tumor Suppressor Protein p53 ; genetics ; physiology

OBJECTIVESTo identify the inhibition effect of shRNA on the SMYD3 (SET- and MYND-domain containing protein-3) expression in hepatoma cell line HepG2 through gene silencing.

METHODSTwo reverse repeated motifs targeting on the SMYD3 mRNA sequences 267-288, 302-323 respectively, were synthesized and inserted into the mock plasmid pGenesil-1 which expressed EGFP to create recombinant plasmids pGenesil-1-s1 and pGenesil-1-s2. pGenesil-1-hk specific to no SMYD3 mRNA sequence served as a control. After transfection into HepG2 cells, RT-PCR and western blot were applied to identify the down regulation of SMYD3 expression by shRNAs.

RESULTSAll plasmids were constructed successfully. pGenesil-1-s1, pGenesil-1-s2 inhibited the mRNA and protein expression of SMYD3 in HepG2 cells. There was a significant distinction when compared with pGenesil-1-hk and pGenesil-1 (P<0.01).

CONCLUSIONShort hairpin RNAs can efficiently and specifically suppress the expression of SMYD3 in HepG2 cells.

Carcinoma, Hepatocellular ; metabolism ; pathology ; Cell Line, Tumor ; Down-Regulation ; Histone-Lysine N-Methyltransferase ; biosynthesis ; genetics ; Humans ; Liver Neoplasms ; metabolism ; pathology ; RNA Interference ; RNA, Messenger ; biosynthesis ; genetics ; RNA, Small Interfering ; genetics ; Transfection

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

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