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MLL3 is also known as lysine methyltransferase 2C (KMT2C). The mutation of MLL3 can occur in a variety of human cancers, including leukemia, liver cancer, and stomach cancer. The effect of MLL3 in different cancers is also different, for example, MLL3 is carcinogenic in pancreatic and liver cancer, while it acts as a tumor suppressor in acute myeloid leukemia and esophageal squamous cell carcinoma. The effects of genes in tumors depend on certain environment and conditions, and the mechanism of the suppressive effect of MLL3 in leukemia is still not clear. This paper reviews the research progress of the antitumor mechanism of MLL3 in leukemia.
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The reversible and precise temporal and spatial regulation of histone lysine methyltransferases(KMTs)is essential for epigenome homeostasis.The dysregulation of KMTs is associated with tumor initiation,metastasis,chemoresistance,invasiveness,and the immune microenvironment.Therapeutically,their promising effects are being evaluated in diversified preclinical and clinical trials,demonstrating encouraging outcomes in multiple malignancies.In this review,we have updated recent understandings of KMTs'functions and the development of their targeted inhibitors.First,we provide an updated overview of the regulatory roles of several KMT activities in oncogenesis,tumor suppression,and im-mune regulation.In addition,we summarize the current targeting strategies in different cancer types and multiple ongoing clinical trials of combination therapies with KMT inhibitors.In summary,we endeavor to depict the regulation of KMT-mediated epigenetic landscape and provide potential epigenetic targets in the treatment of cancers.
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OBJECTIVES@#Silence of SET domain containing lysine methyltransferase 7 (SET7) alleviates myocardial tissue injury caused by ischemia-reperfusion. But the effects of SET7 on angiotensin II (Ang II)-induced myocardial fibroblast proliferation and the collagen synthesis are not clear. The purpose of this study was to explore the effect of SET7 on the proliferation and collagen synthesis of myocardial fibroblasts and its mechanisms.@*METHODS@#Myocardial fibroblasts were isolated and identified by immunofluorescence. Myocardial fibroblasts were randomly divided into 4 groups: a control group (cells were normally cultured), an Ang II group (cells were treated with 100 nmol/L Ang II for 24 h), a siCtrl group (cells were transfected with siRNA control and were then treated with 100 nmol/L Ang II for 24 h), and a siSET7 group (cells were transfected with siRNA SET7 and were then treated with 100 nmol/L Ang II for 24 h). Cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to evaluate cell proliferation. Real-time PCR was used to detect the mRNA levels of SET7, collagen I, collagen III, and α-smooth muscle actin (α-SMA). Western blotting was used to detect the protein expression of SET7, collagen I, collagen III, α-SMA, sonic hedgehog (Shh), ptched1 (Ptch1), and glioma-associated oncogene homolog 1 (Gli1).@*RESULTS@#Fluorescence microscopy showed positive vimentin staining, and myocardial fibroblasts were in good condition. As compared to the control group, the mRNA and protein levels of SET7 in the Ang II group were significantly upregulated; cell proliferation rate and EdU fluorescence intensity in the Ang II group were significantly increased; the mRNA and protein levels of collagen I, collagen III, and α-SMA were significantly upregulated (all @*CONCLUSIONS@#Silence of SET7 gene inhibits Ang II-induced proliferation and collagen synthesis of myocardial fibroblasts. Shh signaling pathway may be involved in this process.
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Angiotensina II/farmacologia , Proliferação de Células , Células Cultivadas , Colágeno/genética , Fibroblastos , Proteínas HedgehogRESUMO
@# Objective: To analyze the mutation of target genes in extranodal natural killer/T-cell lymphoma (ENKTL) by using nextgeneration sequencing, and to explore its relationship with prognosis and clinical characteristics, as to provide evidence for the pathogenesis, clinical diagnosis and targeted therapy of ENKTL. Methods: According to previous literature reports, the genes whose mutations can affect the development of lymphoma were selected as the target genes for this study. 29 patients with ENKTL, who were newly diagnosed at the Fourth Hospital of Hebei Medical University from August 2010 to October 2018, were selected for this study. The mutation of 9 target genes in the specimen was detected by thenext-generationsequencingtechnology.Therelationshipsamongclinicalfeatures,diseaseprognosisandmutationofthetargetgeneswereanalyzedbySPSS21.0statisticalsoftware.Results： ：Ninetargetgenes were were screened. AT-rich interactive-domain 1A(ARID1A) gene showed the highest mutation rate in ENKTL (10 cases, 34.48%) followedbylysinemethyltransferase2D(KMT2D)gene(31.03%)andtumorprotein P53 (TP53) gene (24.13%). Kaplan-Meier survival analysis showed that the overall survival of ENKTL patients with KMT2D gene wild type was significantly better than patients with KMT2D gene mutation (P=0.006). The KMT2D gene mutation was found to besignificantlyrelatedtoclinicalstage,CRP,albumin,lymphocyte count and Ki67 expression in ENKTL patients (all P<0.05). COX regression analysis showed that KMT2D gene mutation was an independent adverse prognostic factor (P<0.05). Conclusion: The KMT2D gene has a high mutant frequency in ENKTL and is associated with patients’prognosis, suggesting that KMT2D gene plays an important role in the initiation and development of ENKTL. It could be used as a clinical therapeutic target for ENKTL.
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Protein lysine methylation is a prevalent post-translational modification (PTM) and plays critical roles in all domains of life. However, its extent and function in photosynthetic organisms are still largely unknown. Cyanobacteria are a large group of prokaryotes that carry out oxygenic photosynthesis and are applied extensively in studies of photosynthetic mechanisms and environmental adaptation. Here we integrated propionylation of monomethylated proteins, enrichment of the modified peptides, and mass spectrometry (MS) analysis to identify monomethylated proteins in Synechocystis sp. PCC 6803 (Synechocystis). Overall, we identified 376 monomethylation sites in 270 proteins, with numerous monomethylated proteins participating in photosynthesis and carbon metabolism. We subsequently demonstrated that CpcM, a previously identified asparagine methyltransferase in Synechocystis, could catalyze lysine monomethylation of the potential aspartate aminotransferase Sll0480 both in vivo and in vitro and regulate the enzyme activity of Sll0480. The loss of CpcM led to decreases in the maximum quantum yield in primary photosystem II (PSII) and the efficiency of energy transfer during the photosynthetic reaction in Synechocystis. We report the first lysine monomethylome in a photosynthetic organism and present a critical database for functional analyses of monomethylation in cyanobacteria. The large number of monomethylated proteins and the identification of CpcM as the lysine methyltransferase in cyanobacteria suggest that reversible methylation may influence the metabolic process and photosynthesis in both cyanobacteria and plants.