BRD4: An emerging prospective therapeutic target in glioma
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ABSTRACT:
SUBMITTER: Yang H
PROVIDER: S-EPMC8010576 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeIncreasing evidence has revealed that nicotinamide N-methyltransferase (NNMT) is a key factor influencing the prognosis of tumors. The present study aimed to investigate the role of NNMT in glioma and to elucidate the associated functional mechanisms.MethodsClinical samples were analyzed by immunohistochemical staining and Western blotting to evaluate NNMT expression in glioma and normal brain tissues. The correlation between NNMT expression and glioma was analyzed using the Cancer Genome Atlas (TCGA) database. Additionally, NNMT was knocked down in two types of glioma cells, U87 and U251, to evaluate the invasive ability of these cells. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate NNMT knockdown in the cells. Furthermore, ELISA was used to determine the balance between nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide hydrogen (NAD/NADH ratio), which verified the altered methylation patterns in the cells. The glioma xenograft mouse models were used to verify the regulatory role of NNMT, GAP43, and SIRT1.ResultsAnalysis based on our clinical glioma samples and TCGA database revealed that overexpression of NNMT was associated with poor prognosis of patients. Knockdown of NNMT reduced the invasive ability of glioma cells, and downregulation of its downstream protein GAP43 occurred due to altered cellular methylation caused by NNMT overexpression. Gene Set Enrichment Analysis confirmed that NNMT modulated the NAD-related signaling pathway and showed a negative association between NNMT and SIRT1. Moreover, the regulatory roles of NNMT, GAP43, and SIRT1 were confirmed in glioma xenograft mouse models.ConclusionOverexpression of NNMT causes abnormal DNA methylation through regulation of the NAD/NADH ratio, which in turn leads to the downregulation of GAP43 and SIRT1, eventually altering the biological behavior of tumor cells.
| S-EPMC9316405 | biostudies-literature
Project description:Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.
| S-EPMC4697417 | biostudies-literature
Project description:Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3' end processing, pre-replication complex assembly and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers, ranging from 5% to 15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with MYC, EWS/FLI and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.
| S-EPMC6242340 | biostudies-literature
Project description:BACKGROUND:Nonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA. METHODS:The expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes. RESULTS:Immunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis. CONCLUSION:In this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.
| S-EPMC7594556 | biostudies-literature
Project description:Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention.
| S-EPMC3328300 | biostudies-literature
Project description:Glioma is the most common type of intracranial malignant tumor, with a great recurrence rate due to its infiltrative growth, treatment resistance, intra- and intertumoral genetic heterogeneity. Recently, accumulating studies have illustrated that activated aerobic glycolysis participated in various cellular and clinical activities of glioma, thus influencing the efficacy of radiotherapy and chemotherapy. However, the glycolytic process is too complicated and ambiguous to serve as a novel therapy for glioma. In this review, we generalized the implication of key enzymes, glucose transporters (GLUTs), signalings and transcription factors in the glycolytic process of glioma. In addition, we summarized therapeutic interventions via the above aspects and discussed promising clinical applications for glioma.
| S-EPMC7371605 | biostudies-literature
Project description:Purpose of reviewDiffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem malignancy. Despite advances in understanding of the molecular underpinnings of the tumor in the past decade, the dismal prognosis of DIPG has thus far remained unchanged. This review seeks to highlight promising therapeutic targets within three arenas: DIPG cell-intrinsic vulnerabilities, immunotherapeutic approaches to tumor clearance, and microenvironmental dependencies that promote tumor growth.Recent findingsPromising therapeutic strategies from recent studies include epigenetic modifying agents such as histone deacetylase inhibitors, bromodomain and extra-terminal motif (BET) protein inhibitors, and CDK7 inhibitors. Tumor-specific immunotherapies are emerging. Key interactions between DIPG and normal brain cells are coming to light, and targeting critical microenvironmental mechanisms driving DIPG growth in the developing childhood brain represents a new direction for therapy.SummarySeveral DIPG treatment strategies are being evaluated in early clinical trials. Ultimately, we suspect that a multifaceted therapeutic approach utilizing cell-intrinsic, microenvironmental, and immunotherapeutic targets will be necessary for eradicating DIPG.
| S-EPMC7242222 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is a major global health problem and its treatment options have been limited. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor important for various cellular processes. Overexpression and constitutive activation of STAT3 have been frequently found in HCC and associated with poor prognosis. Ample evidence has shown that STAT3 plays pivotal roles in the initiation, progression, metastasis and immune suppression of HCC. Thus, STAT3 has attracted attention as a novel therapeutic target in HCC. Clinical trials have investigated STAT3-targeted therapeutics either as monotherapy or in combination with chemotherapeutic agents, immune checkpoint inhibitors and alternative targeted drugs. Some of these studies have yielded encouraging results. Particularly, napabucasin-a cancer stemness inhibitor targeting STAT3-driven gene transcription-has stood out with its promising clinical efficacy and safety profile. Nonetheless, clinical investigations of STAT3-targeted therapies in HCC are limited and more efforts are strongly urged to evaluate their clinical performance in HCC. Here, we provide a comprehensive review of the roles of STAT3 in HCC and follow by comprehensive analysis of STAT3 targeted strategies.
| S-EPMC6895841 | biostudies-literature
Project description:Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma (LAC). KRAS mutations are a major driver of LAC, and are closely related to cigarette smoking, unlike mutations in the epidermal growth factor receptor (EGFR) which arise in never-smokers. Although the past two decades have seen fundamental progress in the treatment and diagnosis of NSCLC, NSCLC still is predominantly diagnosed at an advanced stage when therapeutic interventions are mostly palliative. A disintegrin and metalloproteinase 17 (ADAM17), also known as tumour necrosis factor-? (TNF?)-converting enzyme (TACE), is responsible for the protease-driven shedding of more than 70 membrane-tethered cytokines, growth factors and cell surface receptors. Among these, the soluble interleukin-6 receptor (sIL-6R), which drives pro-inflammatory and pro-tumourigenic IL-6 trans-signaling, along with several EGFR family ligands, are the best characterised. This large repertoire of substrates processed by ADAM17 places it as a pivotal orchestrator of a myriad of physiological and pathological processes associated with the initiation and/or progression of cancer, such as cell proliferation, survival, regeneration, differentiation and inflammation. In this review, we discuss recent research implicating ADAM17 as a key player in the development of LAC, and highlight the potential of ADAM17 inhibition as a promising therapeutic strategy to tackle this deadly malignancy.
| S-EPMC6769596 | biostudies-literature
Project description:Pericytes are functional components of the neurovascular unit (NVU) that are located around the blood vessels, and their roles in the regulation of cerebral health and diseases has been reported. Currently, the potential properties of pericytes as emerging therapeutic targets for cerebrovascular diseases have attracted considerable attention. Nonetheless, few reviews have comprehensively discussed pericytes and their roles in cerebrovascular diseases. Therefore, in this review, we not only summarized and described the basic characteristics of pericytes but also focused on clarifying the new understanding about the roles of pericytes in the pathogenesis of cerebrovascular diseases, including white matter injury (WMI), hypoxic-ischemic brain damage, depression, neovascular insufficiency disease, and Alzheimer's disease (AD). Furthermore, we summarized the current therapeutic strategies targeting pericytes for cerebrovascular diseases. Collectively, this review is aimed at providing a comprehensive understanding of pericytes and new insights about the use of pericytes as novel therapeutic targets for cerebrovascular diseases.
| S-EPMC6882740 | biostudies-literature