Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ambient air particulate matter (PM) induces senescence in human skin cells. However, the underlying mechanisms remain largely unknown. We investigated how epigenetic regulatory mechanisms participate in cellular senescence induced by PM with a diameter <2.5 (PM2.5) in human keratinocytes and mouse skin tissues. PM2.5-treated cells exhibited characteristics of cellular senescence. PM2.5 induced a decrease in DNA methyltransferase (DNMT) expression and an increase in DNA demethylase (ten-eleven translocation; TET) expression, leading to hypomethylation of the p16INK4A promoter region. In addition, PM2.5 led to a decrease in polycomb EZH2 histone methyltransferase expression, whereas the expression of the epigenetic transcriptional activator MLL1 increased. Furthermore, binding of DNMT1, DNMT3B, and EZH2 to the promoter region of p16INK4A decreased in PM2.5-treated keratinocytes, whereas TET1 and MLL1 binding increased, leading to decreased histone H3 lysine 27 trimethylation (H3K27Me3) and increased H3K4Me3 in the promoter of p16INK4A. PM2.5-induced senescence involved aryl hydrocarbon receptor (AhR)-induced reactive oxygen species (ROS) production. ROS scavenging dampened PM2.5-induced cellular senescence through regulation of DNA and histone methylation. Altogether, our work shows that skin senescence induced by environmental PM2.5 occurs through ROS-dependent the epigenetic modification of senescence-associated gene expression. Our findings provide information for the design of preventive and therapeutic strategies against skin senescence, particularly in light of the increasing problem of PM2.5 exposure due to air pollution.
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PMID:Particulate matter-induced senescence of skin keratinocytes involves oxidative stress-dependent epigenetic modifications. 3155 8

Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric di-methylation of arginine residues in histones H3 and H4, marks that are generally associated with transcriptional repression. However, we found that PRMT5 inhibition or depletion led to more genes being downregulated than upregulated, indicating that PRMT5 can also act as a transcriptional activator. Indeed, the global level of histone H3K27me3 increases in PRMT5 deficient cells. Although PRMT5 does not directly affect PRC2 enzymatic activity, methylation of histone H3 by PRMT5 abrogates its subsequent methylation by PRC2. Treating AML cells with an EZH2 inhibitor partially restored the expression of approximately 50% of the genes that are initially downregulated by PRMT5 inhibition, suggesting that the increased H3K27me3 could directly or indirectly contribute to the transcription repression of these genes. Indeed, ChIP-sequencing analysis confirmed an increase in the H3K27me3 level at the promoter region of a quarter of these genes in PRMT5-inhibited cells. Interestingly, the anti-proliferative effect of PRMT5 inhibition was also partially rescued by treatment with an EZH2 inhibitor in several leukemia cell lines. Thus, PRMT5-mediated crosstalk between histone marks contributes to its functional effects.
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PMID:PRMT5-mediated histone arginine methylation antagonizes transcriptional repression by polycomb complex PRC2. 3202 19

Multiple myeloma (MM) is among the most intractable of malignancies and is characterized by uncontrolled growth of malignant plasma cells in the bone marrow (BM). Elucidation of the mechanisms underlying cell adhesion-mediated drug resistance (CAM-DR) may prolong remission and ultimately improve the survival of MM patients. Toward this goal, we identified trimethylation of histone H3 at lysine-27 (H3K27me3) as a critical histone modification associated with CAM-DR. Cell adhesion counteracted drug-induced hypermethylation of H3K27 via inhibiting phosphorylation of enhancer of zeste homolog 2 (EZH2), and promoted sustained expression of anti-apoptotic genes. In addition, we found that CD180, a non-canonical lipopolysaccharide (LPS) receptor, was markedly up-regulated in response to adherence and/or hypoxic conditions. Bacterial LPS enhanced the growth of MM cells both in vitro and in vivo, correlating with expression of CD180. Promoter analyses identified Ikaros (IKZF1) as a pivotal transcriptional activator of the CD180 gene; expression of CD180 was activated via cell adhesion- and/or hypoxia-mediated increases in IKZF1 expression. Administration of lenalidomide prevented the LPS-triggered activation of MM cells by targeting CD180. Taken together, our results suggest that lenalidomide-mediated prevention of LPS-triggered disease progression may be an effective means for prolonging survival in patients with MM.
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PMID:[Toll-like receptor CD180 and the bone marrow microenvironment as therapeutic targets in multiple myeloma]. 3275 72

Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at their promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here, we show that SUMOylation, a posttranslational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacologic inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin, which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 was positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches. SIGNIFICANCE: These findings provide important biological insights into the mechanism of EZH2 overexpression in cancers and suggest that inhibiting SUMOylation may improve current cancer therapeutic approaches.
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PMID:SUMOylation of E2F1 Regulates Expression of EZH2. 3281 57

Recent investigation of microRNAs on chronic pain has developed a breakthrough in neuropathic pain management. In the present study, decreased expression of miR-30a-3p was reported using qRT-PCR analysis and loss of miR-30a-3p promoted neuropathic pain progression in sciatic nerve chronic constrictive injury rats through determining the pain threshold. We predicted miR-30a-3p could target E-cadherin transcriptional activator (EP300) via bioinformatics analysis. Meanwhile, we found that brain-derived neurotrophic factor (BDNF) is involved in neuropathic pain. Here, we exhibited that EP300 epigenetically up-regulated BDNF via enhancing acetylated histone H3 and H4 on the promoter. For another, miR-30a-3p was able to modify the level of BDNF and acetylated histone H3 and H4. Loss of miR-30a-3p enhanced EP300 and BDNF colocalization in CCI rats. Subsequently, it was shown that increased EP300 induced neuropathic pain by an enhancement of neuronal BDNF level in vivo. To sum up, it was revealed that epigenetic modification of BDNF promoted neuropathic pain via EP300 induced by miR-30a-3p in CCI rats.
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PMID:Epigenetic modification of BDNF mediates neuropathic pain via miR-30a-3p/EP300 axis in CCI rats. 3310 39


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