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American Journal of Cancer Research 2021SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1, ESET, KMT1E) is a H3K9 methyltransferase involved in gene silencing. In recent years, SETDB1 has been... (Review)
Review
SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1, ESET, KMT1E) is a H3K9 methyltransferase involved in gene silencing. In recent years, SETDB1 has been implicated as an oncogene in various cancers, highlighting a critical need to better understand the mechanisms underlying SETDB1 amplification, overexpression, and activation. In the following review, we first examine the history of SETDB1, starting from its discovery in 1999 and ending with recent findings. We follow with an outline of the structure and subcellular location of SETDB1, as well as potential mechanisms for regulation of its nuclear transport. Subsequently, we introduce SETDB1's various functions, including its roles in promyelocytic leukemia nuclear body (PML-NB) formation, the methylation and activation of Akt, the silencing of the androgen receptor (AR) gene, retroelement silencing, the inhibition of tumor suppressor p53, and its role in promoting intestinal differentiation and survival. The Cancer Cell Line Encyclopedia (CCLE) screened SETDB1 dependency in 796 cancer cell lines, identifying SETDB1 as a common essential gene in 531 of them, demonstrating that SETDB1 expression is critical for the survival of the majority of cancers. Therefore, we provide a detailed review of the oncogenic effects of SETDB1 overexpression in breast cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, acute myeloid leukemia, glioma, melanoma, pancreatic ductal adenocarcinoma, liver cancer, nasopharyngeal carcinoma, gastric carcinoma, and endometrial cancer. Accordingly, we review several methods that have been used to target SETDB1, such as using Mithramycin A, Mithralog EC-8042, 3'-deazaneplanocin A (DZNep), and paclitaxel. Finally, we conclude by highlighting remaining gaps in knowledge and challenges surrounding SETDB1. Ultimately, our review captures the wide scope of findings on SETDB1's history, function, its implications in cancer, and provides suggestions for future research in the field.
PubMed: 34094655
DOI: No ID Found -
Toxicology and Applied Pharmacology Aug 2021Triptolide (TP), a primary bioactive ingredient isolated from the traditional Chinese herbal medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted great...
Triptolide (TP), a primary bioactive ingredient isolated from the traditional Chinese herbal medicine Tripterygium wilfordii Hook. F. (TWHF), has attracted great interest for its therapeutic biological activities in inflammation and autoimmune disease. However, its clinical use is limited by severe testicular toxicity, and the underlying mechanism has not been elucidated. Our preliminary evidence demonstrated that TP disrupted glucose metabolism and caused testicular toxicity. During spermatogenesis, Sertoli cells (SCs) provide lactate as an energy source to germ cells by glycolysis. The transcription factors GATA-binding protein 4 (GATA4) and specificity protein 1 (Sp1) can regulate glycolysis. Based on this evidence, we speculate that TP causes abnormal glycolysis in SCs by influencing the expression of the transcription factors GATA4 and Sp1. The mechanism of TP-induced testicular toxicity was investigated in vitro and in vivo. The data indicated that TP decreased glucose consumption, lactate production, and the mRNA levels of glycolysis-related transporters and enzymes. TP also downregulated the protein expression of the transcription factors GATA4 and Sp1, as well as the glycolytic enzyme phosphofructokinase platelet (PFKP). Phosphorylated GATA4 and nuclear GATA4 protein levels were reduced in a dose- and time-dependent manner after TP incubation. Similar effects were observed in shGata4-treated TM4 cells and BALB/c mice administered 0.4 mg/kg TP for 28 days, and glycolysis was also inhibited. Gata4 knockdown downregulated Sp1 and PFKP expression. Furthermore, the Sp1 inhibitor plicamycin inhibited PFKP protein levels in TM4 cells. In conclusion, TP inhibited GATA4-mediated glycolysis by suppressing Sp1-dependent PFKP expression in SCs and caused testicular toxicity.
Topics: Animals; Cell Line; Cell Proliferation; Cell Survival; Diterpenes; Down-Regulation; Epoxy Compounds; GATA4 Transcription Factor; Gene Expression Regulation; Glycolysis; HEK293 Cells; Humans; Male; Mice; Mice, Inbred ICR; Phenanthrenes; Phosphofructokinase-1, Type C; Sertoli Cells; Signal Transduction; Sp1 Transcription Factor
PubMed: 34087332
DOI: 10.1016/j.taap.2021.115606 -
Seminars in Cancer Biology Nov 2022Cancer stands in the frontline among leading killers worldwide and the annual mortality rate is expected to reach 16.4 million by 2040. Humans suffer from about 200... (Review)
Review
Cancer stands in the frontline among leading killers worldwide and the annual mortality rate is expected to reach 16.4 million by 2040. Humans suffer from about 200 different types of cancers and many of them have a small number of approved therapeutic agents. Moreover, several types of major cancers are diagnosed at advanced stages as a result of which the existing therapies have limited efficacy against them and contribute to a dismal prognosis. Therefore, it is essential to develop novel potent anticancer agents to counteract cancer-driven lethality. Natural sources such as bacteria, plants, fungi, and marine microorganisms have been serving as an inexhaustible source of anticancer agents. Notably, over 13,000 natural compounds endowed with different pharmacological properties have been isolated from different bacterial sources. In the present article, we have discussed about the importance of natural products, with special emphasis on bacterial metabolites for cancer therapy. Subsequently, we have comprehensively discussed the various sources, mechanisms of action, toxicity issues, and off-target effects of clinically used anticancer drugs (such as actinomycin D, bleomycin, carfilzomib, doxorubicin, ixabepilone, mitomycin C, pentostatin, rapalogs, and romidepsin) that have been derived from different bacteria. Furthermore, we have also discussed some of the major secondary metabolites (antimycins, chartreusin, elsamicins, geldanamycin, monensin, plicamycin, prodigiosin, rebeccamycin, salinomycin, and salinosporamide) that are currently in the clinical trials or which have demonstrated potent anticancer activity in preclinical models. Besides, we have elaborated on the application of metagenomics in drug discovery and briefly described about anticancer agents (bryostatin 1 and ET-743) identified through the metagenomics approach.
Topics: Humans; Antineoplastic Agents; Neoplasms; Biological Products; Fungi; Bacteria
PubMed: 33979675
DOI: 10.1016/j.semcancer.2021.05.006 -
Structure (London, England : 1993) May 2021Fusion products with the ETS family of transcription factors play critical roles in the etiology of several cancers. In this issue of Structure, Hou et al. (2020)...
Fusion products with the ETS family of transcription factors play critical roles in the etiology of several cancers. In this issue of Structure, Hou et al. (2020) provide insight into allosteric mechanisms by which mithramycin and its analogs perturb protein-DNA interactions in higher-order complexes at a DNA enhancer site.
Topics: Base Sequence; DNA; Plicamycin; Transcription Factors
PubMed: 33961789
DOI: 10.1016/j.str.2021.03.010 -
Journal of Clinical Medicine Mar 2021Sarcomas are aggressive tumors which often show a poor response to current treatments. As a promising therapeutic alternative, we focused on mithramycin (MTM), a natural...
Sarcomas are aggressive tumors which often show a poor response to current treatments. As a promising therapeutic alternative, we focused on mithramycin (MTM), a natural antibiotic with a promising anti-tumor activity but also a relevant systemic toxicity. Therefore, the encapsulation of MTM in nano-delivery systems may represent a way to increase its therapeutic window. Here, we designed novel transfersomes and PLGA polymeric micelles by combining different membrane components (phosphatidylcholine, Span 60, Tween 20 and cholesterol) to optimize the nanoparticle size, polydispersity index (PDI) and encapsulation efficiency (EE). Using both thin film hydration and the ethanol injection methods we obtained MTM-loaded transferosomes displaying an optimal hydrodynamic diameter of 100-130 nm and EE values higher than 50%. Additionally, we used the emulsion/solvent evaporation method to synthesize polymeric micelles with a mean size of 228 nm and a narrow PDI, capable of encapsulating MTM with EE values up to 87%. These MTM nano-delivery systems mimicked the potent anti-tumor activity of free MTM, both in adherent and cancer stem cell-enriched tumorsphere cultures of myxoid liposarcoma and chondrosarcoma models. Similarly to free MTM, nanocarrier-delivered MTM efficiently inhibits the signaling mediated by the pro-oncogenic factor SP1. In summary, we provide new formulations for the efficient encapsulation of MTM which may constitute a safer delivering alternative to be explored in future clinical uses.
PubMed: 33806182
DOI: 10.3390/jcm10071358 -
Leukemia Nov 2021T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including...
T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1. However, most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTM32E) to suppress CLL IL-10. MTM32E treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the Eμ-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and increased CD8 T-cell proliferation, effector and memory cell prevalence, and interferon-γ production. When combined with ICB, suppression of IL-10 improved responses to anti-PD-L1 as shown by a 4.5-fold decrease in CLL cell burden compared to anti-PD-L1 alone. Combination therapy also produced more interferon-γ, cytotoxic effector KLRG1, and memory CD8 T-cells, and fewer exhausted T-cells. Since current therapies for CLL do not target IL-10, this provides a novel strategy to improve immunotherapies.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Case-Control Studies; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors; Interleukin-10; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Mice; Mice, Inbred NOD; Mice, SCID; Plicamycin; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33731852
DOI: 10.1038/s41375-021-01217-1 -
Inflammation Aug 2021The present study was aimed to investigate the phototherapy effect with low-level laser on human bronchial epithelial cells activated by cigarette smoke extract (CSE)....
The MAPKinase Signaling and the Stimulatory Protein-1 (Sp1) Transcription Factor Are Involved in the Phototherapy Effect on Cytokines Secretion from Human Bronchial Epithelial Cells Stimulated with Cigarette Smoke Extract.
The present study was aimed to investigate the phototherapy effect with low-level laser on human bronchial epithelial cells activated by cigarette smoke extract (CSE). Phototherapy has been reported to actuate positively for controlling the generation/release of anti-inflammatory and pro-inflammatory mediators from different cellular type activated by distinct stimuli. It is not known whether the IL-8 and IL-10 release from CSE-stimulated human bronchial epithelium (BEAS) cells can be influenced by phototherapy. Human bronchial epithelial cell (BEAS) line was cultured in a medium with CSE and irradiated (660 nm) at 9 J. Apoptosis index was standardized with Annexin V and the cellular viability was evaluated by MTT. IL-8, IL-10, cAMP, and NF-κB were measured by ELISA as well as the Sp1, JNK, ERK1/2, and p38MAPK. Phototherapy effect was studied in the presence of mithramycin or the inhibitors of JNK or ERK. The IL-8, cAMP, NF-κB, JNK, p38, and ERK1/2 were downregulated by phototherapy. Both the JNK and the ERK inhibitors potentiated the phototherapy effect on IL-8 as well as on cAMP secretion from BEAS. On the contrary, IL-10 and Sp1 were upregulated by phototherapy. The mithramycin blocked the phototherapy effect on IL-10. The results suggest that phototherapy has a dual effect on BEAS cells because it downregulates the IL-8 secretion by interfering with CSE-mediated signaling pathways, and oppositely upregulates the IL-10 secretion through of Sp1 transcription factor. The manuscript provides evidence that the phototherapy can interfere with MAPK signaling via cAMP in order to attenuate the IL-8 secretion from CSE-stimulated BEAS. In addition, the present study showed that phototherapy effect is driven to downregulation of the both the IL-8 and the ROS secretion and at the same time the upregulation of IL-10 secretion. Besides it, the increase of Sp-1 transcription factor was crucial for laser effect in upregulating the IL-10 secretion. The dexamethasone corticoid produces a significant inhibitory effect on IL-8 as well as ROS secretion, but on the other hand, the corticoid blocked the IL-10 secretion. Taking it into consideration, it is reasonable to suggest that the beneficial effect of laser therapy on lung diseases involves its action on unbalance between pro-inflammatory and anti-inflammatory mediators secreted by human bronchial epithelial cells through different signaling pathway.
Topics: Bronchi; Cell Line; Cigarette Smoking; Cytokines; Humans; Mitogen-Activated Protein Kinase Kinases; Phototherapy; Respiratory Mucosa; Smoke; Sp1 Transcription Factor; Nicotiana
PubMed: 33730343
DOI: 10.1007/s10753-021-01448-5 -
Frontiers in Cardiovascular Medicine 2021Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and organic stenosis. It has been demonstrated that endothelin-1 (ET-1) induces...
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vasoconstriction and organic stenosis. It has been demonstrated that endothelin-1 (ET-1) induces pulmonary vasoconstriction through the activation of RhoA. In addition, a gene mutation of activin receptor-like kinase (ACVRL)-1 is recognized in PAH patients. However, little is known about the association between ET-1 and ACVRL-1. In the present study, we aimed to investigate the effect of ET-1 on ACVRL-1 expression and delineate the involvement of the G/RhoA/Rho kinase pathway. ET-1 was added to culture medium of human pulmonary arterial endothelial cells (PAECs). Pre-treatment with pertussis toxin (PTX) or exoenzyme C3 transferase (C3T) was performed for inhibition of G or RhoA, respectively. Rho kinase was inhibited by Y27632. Mithramycin A was used for inhibition of Sp-1, which is a transcriptional factor of ACVRL-1. The active form of RhoA (GTP-RhoA) was assessed by pull-down assay. ACVRL-1 expression was increased by ET-1 in the PAECs. Pull-down assay revealed that ET-1 induced GTP-loading of RhoA, which was suppressed by pre-treatment with PTX or C3T. Further, PTX, C3T, and Y27632 suppressed the ET-1-induced ACVRL-1 expression. ET-1 increased the activity of the ACVRL-1 promoter and stabilized the ACVRL-1 mRNA. Sp-1 peaked 15 min after adding ET-1 to the PAECs. PTX and C3T prevented the increase of Sp-1 induced by ET-1. Inhibition of Sp-1 by mithramycin A suppressed ET-1-induced ACVRL-1 upregulation. The present study demonstrated that ET-1 increases ACVRL-1 expression in human PAECs the G/RhoA/Rho kinase pathway with the involvement of Sp-1.
PubMed: 33708809
DOI: 10.3389/fcvm.2021.648981 -
Critical Reviews in Oncogenesis 2020Specificity protein (Sp) transcription factors regulate the expression of genes associated with several cellular processes and play a critical role in early development.... (Review)
Review
Specificity protein (Sp) transcription factors regulate the expression of genes associated with several cellular processes and play a critical role in early development. Typically, Sp protein expression decreases with age in healthy adults. Research has shown that Sp proteins can impact the development and transformation of cancer cells and other oncogenic processes, including survival, proliferation, spread, and metastasis. Among the Sp proteins, Sp1, Sp3, and Sp4 have been the main targets of study as they are shown to be highly expressed in cancer cells compared to healthy cells. Increased levels of Sp1 are correlated with poor prognosis in some malignancies, including gastrointestinal cancers. In this review, we discuss the role of Sp transcription factors and examine their activities as pro-oncogenic factors in esophageal cancer (EC). Other aspects presented in this review are potential therapeutic options for EC that target Sp1. We summarize the published information on preclinical results using mithramycin and tolfenamic acid.
Topics: Carcinogenesis; Esophageal Neoplasms; Humans; Plicamycin; Prognosis; Risk Factors; Sp Transcription Factors; ortho-Aminobenzoates
PubMed: 33639062
DOI: 10.1615/CritRevOncog.2020036449 -
In Vitro Cellular & Developmental... Mar 2021Specific protein 1 (SP1) might act as a critical transcription regulator in myocardial infarction (MI), but little evidence about its function in regulating cardiac...
Specific protein 1 (SP1) might act as a critical transcription regulator in myocardial infarction (MI), but little evidence about its function in regulating cardiac apoptosis, a major cause of MI development, has been revealed. This study tried to investigate the role of SP1 in MI and its interaction with poly-ADP-ribose polymerase (PARP)-1 by using SP1 inhibitor, mithramycin A (mithA). Primary mouse cardiomyocytes and commercial mouse cardiomyocytes were subjected to mithA treatment under hypoxia conditions, while cell viability, Nix promoter activity, and its expression were detected correspondingly. PARP overexpression and knockdown were conducted, respectively, in mithA-treated and SP1-overexpressing cells. Co-immunoprecipitation was used to verify the interaction between PARP and SP1. For in vivo experiments, mithA administration was performed after the injections of adenovirus for PARP overexpression, and then, MI introduction was carried out. Infarct size and lactate dehydrogenase level were measured to assess MI injury. SP1 inhibitor mithA attenuated hypoxia-induced decrease of cell viability and Nix transcriptional activation, which could be inhibited by PARP overexpression. Knockdown of PARP prevented SP1-induced transcription of Nix and cell viability change, and PARP showed direct interaction with SP1. Furthermore, mithA administration reduced MI injuries, while PARP overexpression could suppress the improvement. The cardioprotective role of SP1 inhibitor mithA was demonstrated here expanding the role of SP1 in MI development involving hypoxia-induced cardiac apoptosis. Moreover, PARP acted as a transcriptional coactivator in Nix transcription involving its interaction with SP1.
Topics: Animals; Apoptosis; Cardiotonic Agents; Cell Hypoxia; Cell Survival; Male; Membrane Proteins; Mice, Inbred C57BL; Mitochondrial Proteins; Myocardial Infarction; Myocytes, Cardiac; Plicamycin; Poly(ADP-ribose) Polymerases; Protein Binding; Sp1 Transcription Factor; Transcription, Genetic; Mice
PubMed: 33580416
DOI: 10.1007/s11626-021-00543-z