Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, pointing to DNMT3A as a critically important new tumour suppressor. Here, we review the clinical findings related to DNMT3A, tie these data to insights from basic science studies conducted over the past 20 years and present a roadmap for future research that should advance the agenda for new therapeutic strategies.
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PMID:DNMT3A in haematological malignancies. 2569 34

Early Growth Response 1 (EGR1) is a stress response transcription factor with multiple tumour suppressor roles in breast tissue, whose expression is often lost in breast cancers. We have previously shown that the breast cancer oncogene TBX2 (T-BOX2) interacts with EGR1 to co-repress EGR1-target genes including the breast tumour suppressor NDRG1. Here, we show the mechanistic basis of this TBX2 repression complex. We show that siRNA knockdown of TBX2, EGR1, Heterochromatin Protein 1 (HP1) isoforms and the generic HP1-associated corepressor protein KAP1 all resulted in growth inhibition of TBX2-expressing breast cancer cells. We show that TBX2 interacts with HP1 through a conserved HP1-binding motif in its N-terminus, which in turn leads to the recruitment of KAP1 and other associated proteins. Mutation of the TBX2 HP1 binding domain abrogates the TBX2-HP1 interaction and loss of repression of target genes such as NDRG1. Chromatin-immunoprecipitation (ChIP) assays showed that TBX2 establishes a repressive chromatin mark, specifically H3K9me3, around the NDRG1 proximal promoter coincident with the recruitment of the DNA methyltransferase DNMT3B and histone methyltransferase (HMT) complex components (G9A, Enhancer of Zeste 2 (EZH2) and Suppressor of Zeste 12 (SUZ12)). Knockdown of G9A, EZH2 or SUZ12 resulted in upregulation of TBX2/EGR1 co-regulated targets accompanied by a dramatic inhibition of cell proliferation. We show that a generic inhibitor of HMT activity, DzNep, phenocopies expression of an inducible dominant negative TBX2. Knockdown of TBX2, KAP1 or HP1 inhibited NDRG1 promoter decoration specifically with the H3K9me3 repression mark. Correspondingly, treatment with a G9A inhibitor effectively reversed TBX2 repression of NDRG1 and synergistically downregulated cell proliferation following TBX2 functional inhibition. These data demonstrate that TBX2 promotes suppression of normal growth control mechanisms through recruitment of a large repression complex to EGR1-responsive promoters leading to the uncontrolled proliferation of breast cancer cells.
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PMID:TBX2 interacts with heterochromatin protein 1 to recruit a novel repression complex to EGR1-targeted promoters to drive the proliferation of breast cancer cells. 3125 70

Epigenetics is a kind of heritable change that involves the unaltered DNA sequence and can have effects on gene expression. The regulatory mechanism mainly includes DNA methylation, histone modification and non-coding RNA regulation. DNA methylation is currently the most studied aspect of epigenetics. It is widely present in eukaryotic cells and is the most important epigenetic mark in the regulation of gene expression in the cell. DNA methyltransferase inhibitors (DNMTi) have been increasingly recognized in the field of cancer immunotherapy, have been approved for the treatment of acute myeloid leukaemia (AML) and are widely being used in clinical trials of cancer immunotherapies. DNMTi promote the reactivation of tumour suppressor genes, enhance tumour immunogenicity, and stimulate a variety of immune cells to secrete cytokines that exert cytotoxic effects, promote tumour cell death, including macrophages, natural killer (NK) cells and CD8+ T cells, and upregulate major histocompatibility complex (MHC) class I expression levels. Here, we mainly summarize the epigenetics related to DNMTi and their regulation of the antitumour immune response and DNMTi combined with immuno-therapeutics or histone deacetylase inhibitors to demonstrate the great development potential and clinical application value of DNMTi.
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PMID:DNA Methyltransferase Inhibitors: Catalysts For Antitumour Immune Responses. 3184 94


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