Emerging role of G9a in cancer stemness and promises as a therapeutic target

AbstractThe histone methyltransferase G9a is well-documented for its implication in neoplastic growth. However, recent investigations have demonstrated a key involvement of this chromatin writer in maintaining the self-renewal and tumor-initiating capacities of cancer stem cells (CSCs). Direct inhibition of G9a’s catalytic activity was reported as a promising therapeutic target in multiple preclinical studies. Yet, none of the available pharmacological inhibitors of G9a activity have shown success at the early stages of clinical testing. Here, we discuss central findings of oncogenic expression and activation of G9a in CSCs from different origins, as well as the impact of the suppression of G9a histone methyltransferase activity in such contexts. We will explore the challenges posed by direct and systemic inhibition of G9a activity in the perspective of clinical translation of documented small molecules. Finally, we will discuss recent advances in drug discovery as viable strategies to develop context-specific drugs, selectively targeting G9a in CSC populations.

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The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice

Biology ◽

10.3390/biology9050093 ◽

2020 ◽

Vol 9 (5) ◽

pp. 93 ◽

Cited By ~ 1

Author(s):

Seul Lee ◽

Dong-Cheol Woo ◽

Jeeheon Kang ◽

Moonjin Ra ◽

Ki Hyun Kim ◽

...

Keyword(s):

Liver Disease ◽

Epigenetic Modification ◽

Treatment Options ◽

Histone Methyltransferase ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Promising Therapeutic Target ◽

Alcoholic Fatty Liver Disease ◽

Potential Therapeutics

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

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Children coping with COVID-19: Intersectional understandings of film and media access in a crisis

Film Education Journal ◽

10.14324/fej.04.1.03 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Justine Atkinson ◽

Firdoze Bulbulia

Keyword(s):

South Africa ◽

The Netherlands ◽

Case Studies ◽

Media Access ◽

Specific Focus ◽

Film Education ◽

The World ◽

Context Specific ◽

The Impact

As a result of the global COVID-19 pandemic and resulting lockdowns across the world, digital access has become paramount, as most aspects of education have moved online. Drawing together five case studies located in South Africa, Argentina, the Netherlands, India and Ethiopia, this article assesses the role of film education during the COVID-19 pandemic, with a specific focus on the impacts of digital access. We examine multimodal forms of film education, and how these were used to inform, entertain and educate children during the crisis by the varying work undertaken by the organizations. Applying theories of intersectionality, we address the need for context-specific approaches to film education, focusing upon the impact that the societal and individual contexts had on the dissemination of film education in each country.

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HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14616 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14616-e14616

Author(s):

Francesco Sclafani ◽

Amitesh Chandra Roy ◽

Ian Chau ◽

Andrew Wotherspoon ◽

Clare Peckitt ◽

...

Keyword(s):

Rectal Cancer ◽

High Risk ◽

Cancer Patients ◽

Therapeutic Target ◽

Predictive Biomarker ◽

Secondary Endpoints ◽

Her 2 ◽

Low Prevalence ◽

The Impact

e14616 Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression have been reported. Preclinical data indicate a potential role of HER-2 in mediating resistance of rectal cancer to chemoradiotherapy and cetuximab. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in EXPERT-C. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. In an exploratory analysis, 44 IHC 0/1+ random specimens were tested by B-DISH and HER-2 amplification was found in 3/38 (7.9%, insufficient material in 6 cases). Conclusions: Based on the low prevalence of expression (according to the classical criteria for defining HER-2 positivity) as recorded in EXPERT-C, HER-2 does not appear to represent a useful therapeutic target for high risk rectal cancer. We did not confirm the role of HER-2 as prognostic factor or potential predictive biomarker for cetuximab-based treatment.

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The Role of F11R in Pancreatic Cancer Malignancy and Its Clinical Implication as a Therapeutic Target

10.21203/rs.2.13324/v1 ◽

2019 ◽

Author(s):

Haidi zhang ◽

Chunyan Zhao ◽

Xianhua Hu ◽

Shuai He ◽

Jinchuan Yu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Therapeutic Target ◽

Immunoglobulin Superfamily ◽

Experimental Conditions ◽

Cycle Arrest ◽

Pancreatic Cancer Cells ◽

Promising Therapeutic Target ◽

Cell Invasiveness

Abstract Abstract Background The F11 receptor belongs to the immunoglobulin superfamily and is expressed in epithelial and endothelial cells. F11R mediates the formation of tight junctions between the epithelium and endothelium, and participates in the invasion and metastasis of tumor cells. We have previously shown that the F11R gene is closely related to KRas (P= 0.76), a known therapeutic target for pancreatic cancer (PCa). In recent years, it has been found that F11R is expressed in different tumors and has biological effects.However, according to different tumor cases, different cell lines and experimental conditions, the regulatory results and mechanisms of F11R on tumor are different, even contradictory,and the expression, clinical significance and biological mechanism of F11R in tumor tissues have not been reported in detail. Results To investigate the role of F11R in carcinogenesis of PCa and the potential of F11R as a therapies target for PCa, we silenced F11R (-/-) in the PCa cell line PANC-1 (known to express high levels of KRas) using lentiviral approaches.We found that F11R silencing led to decreased cell proliferation, a loss of cell invasiveness, reduced colony forming ability, cell cycle arrest in G1 phase, cells apoptosis enhanced, and ros enhanced. In vitro data showed that inhibition of F11R decreased proliferation and invasiveness of cancer cells.The present results suggest that F11R may be a promising therapeutic target for PCa. Conclusions This study used bioinformatics combined with gene chip data to find the gene F11R, which is closely related to KRAS gene, and we used lentivirus to package shRNA plasmid to interfere with the gene F11R in pancreatic cancer panc-1 cells. A series of biobehavioral studies indicated the biobehavioral function and malignancy of panc-1 in pancreatic cancer cells with negative regulation of F11R gene.Based on this, we need to continue to clarify the expression of F11R gene in clinical case samples to determine whether F11R gene can be a new therapeutic target for pancreatic cancer.

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N-Glycosylation Facilitates 4-1BB Membrane Localization by Avoiding Its Multimerization

Cells ◽

10.3390/cells11010162 ◽

2022 ◽

Vol 11 (1) ◽

pp. 162

Author(s):

Ruoxuan Sun ◽

Alyssa Min Jung Kim ◽

Allison A. Murray ◽

Seung-Oe Lim

Keyword(s):

Therapeutic Target ◽

Biological Properties ◽

Protein Abundance ◽

Potential Mechanism ◽

Activated T Cells ◽

Ligand Interaction ◽

Cell Immunity ◽

Promising Therapeutic Target ◽

Turn Over ◽

The Impact

Leveraging the T cell immunity against tumors represents a revolutionary type of cancer therapy. 4-1BB is a well-characterized costimulatory immune receptor existing on activated T cells and mediating their proliferation and cytotoxicity under infectious diseases and cancers. Despite the accumulating interest in implementing 4-1BB as a therapeutic target for immune-related disorders, less is known about the pattern of its intracellular behaviors and regulations. It has been previously demonstrated that 4-1BB is heavily modified by N-glycosylation; however, the biological importance of this modification lacks detailed elucidation. Through biochemical, biophysical, and cell-biological approaches, we systematically evaluated the impact of N-glycosylation on the ligand interaction, stability, and localization of 4-1BB. We hereby highlighted that N-glycan functions by preventing the oligomerization of 4-1BB, thus permitting its membrane transportation and fast turn-over. Without N-glycosylation, 4-1BB could be aberrantly accumulated intracellularly and fail to be sufficiently inserted in the membrane. The N-glycosylation-guided intracellular processing of 4-1BB serves as the potential mechanism explicitly modulating the “on” and “off” of 4-1BB through the control of protein abundance. Our study will further solidify the understanding of the biological properties of 4-1BB and facilitate the clinical practice against this promising therapeutic target.

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Vitamin D/VDR in acute kidney injury: a potential therapeutic target

Current Medicinal Chemistry ◽

10.2174/0929867327666201118155625 ◽

2020 ◽

Vol 27 ◽

Author(s):

Siqing Jiang ◽

Lihua Huang ◽

Wei Zhang ◽

Hao Zhang

Keyword(s):

Vitamin D ◽

Acute Kidney Injury ◽

Therapeutic Target ◽

Poor Prognosis ◽

Therapeutic Potential ◽

Kidney Injury ◽

Potential Therapeutic Target ◽

Promising Therapeutic Target ◽

Incidence And Mortality

: Despite many strategies and parameters used in clinical practice, the incidence and mortality of acute kidney injury (AKI) are still high with poor prognosis. With the development of molecular biology, the role of vitamin D and vitamin D receptor (VDR) in AKI is drawing increasing attention. Accumulated researches have suggested that Vitamin D deficiency is a risk factor of both clinical and experimental AKI, and vitamin D/VDR could be a promising therapeutic target against AKI. However, more qualitative clinical researches are needed to provide stronger evidence for clinical application of vitamin D and VDR agonists in the future. Issues like the route and dosage of administration also await more attention. The present review aims to summarize the current works on the role of vitamin D/VDR in AKI and try to provide some new insight of its therapeutic potential.

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The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target

Current Neuropharmacology ◽

10.2174/1570159x19666210402102232 ◽

2021 ◽

Vol 19 ◽

Author(s):

Yu Cheng ◽

Wuqiong Zhang ◽

Yue Li ◽

Ting Jiang ◽

Buhajar Mamat ◽

...

Keyword(s):

Therapeutic Target ◽

Molecular Mechanisms ◽

Brain Diseases ◽

Mammalian Brain ◽

Acid Sensing Ion Channels ◽

Promising Therapeutic Target ◽

Pathological Mechanism ◽

Tissue Acidosis ◽

Epileptogenic Foci

Background: Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. This said, its roles in epileptogenesis remain unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis. Methods: Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: "Acid-sensing ion channels 1a" or "ASIC1a" and "epilepsy" or "seizure". Results: The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy. Conclusion:This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to further elucidate the role of ASIC1a in epilepsy.

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Caveolin-1: A promising therapeutic target for diverse diseases

Current Molecular Pharmacology ◽

10.2174/1874467214666211130155902 ◽

2021 ◽

Vol 14 ◽

Author(s):

Shivani Gokani ◽

Lokesh Kumar Bhatt

Keyword(s):

Viral Entry ◽

Therapeutic Target ◽

Hippocampal Neurons ◽

Physiological Role ◽

Clinical Applications ◽

Caveolin 1 ◽

Patients With Cancer ◽

Cellular Events ◽

Promising Therapeutic Target

: The plasma membrane of eukaryotic cells contains small flask-shaped invaginations known as caveolae that are involved in the regulation of cellular signaling. Caveolin-1 is a 21-24kDa protein localized in the caveolar membrane. Caveolin-1 (Cav-1) has been considered as a master regulator among the various signaling molecules. It has been emerging as a chief protein regulating cellular events associated with homeostasis, caveolae formation, and caveolae trafficking. In addition to the physiological role of cav-1, it has a complex role in the progression of various diseases. Caveolin-1 has been identified as a prognosticator in patients with cancer and has a dual role in tumorigenesis. The expression of Cav-1 in hippocampal neurons and synapses is related to neurodegeneration, cognitive decline, and aging. Despite the ubiquitous association of caveolin-1 in various pathological processes, the mechanisms associated with these events are still unclear. Caveolin-1 has a significant role in various events of the viral cycle, such as viral entry. This review will summarize the role of cav-1 in the development of cancer, neurodegeneration, glaucoma, cardiovascular diseases, and infectious diseases. The therapeutic perspectives involving clinical applications of Caveolin-1 have also been discussed. The understanding of the involvement of caveolin-1 in various diseased states provides insights into how it can be explored as a novel therapeutic target.

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The impact of Mir-9 regulation in normal and malignant hematopoiesis

Oncology Reviews ◽

10.4081/oncol.2018.348 ◽

2018 ◽

Cited By ~ 4

Author(s):

Abbas Khosravi ◽

Shaban Alizadeh ◽

Arsalan Jalili ◽

Reza Shirzad ◽

Najmaldin Saki

Keyword(s):

Prognostic Factor ◽

Therapeutic Target ◽

Prognostic Value ◽

Critical Role ◽

Hematologic Malignancies ◽

Controlling Factors ◽

Treatment Approaches ◽

The Impact ◽

Hematologic Neoplasia

MicroRNA-9 (MiR-9) dysregulation has been observed in various cancers. Recently, MiR-9 is considered to have a part in hematopoiesis and hematologic malignancies. However, its importance in blood neoplasms is not yet well defined. Thus, this study was conducted in order to assess the significance of MiR-9 role in the development of hematologic neoplasia, prognosis, and treatment approaches. We have shown that a large number of MiR-9 targets (such as FOXOs, SIRT1, CCND1, ID2, CCNG1, Ets, and NFkB) play essential roles in leukemogenesis and that it is overexpressed in different leukemias. Our findings indicated MiR-9 downregulation in a majority of leukemias. However, its overexpression was reported in patients with dysregulated MiR-9 controlling factors (such as MLLr). Additionally, prognostic value of MiR-9 has been reported in some types of leukemia. This study generally emphasizes on the critical role of MiR-9 in hematologic malignancies as a prognostic factor and a therapeutic target.

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TRIM Proteins in Colorectal Cancer: TRIM8 as a Promising Therapeutic Target in Chemo Resistance

Biomedicines ◽

10.3390/biomedicines9030241 ◽

2021 ◽

Vol 9 (3) ◽

pp. 241

Author(s):

Flaviana Marzano ◽

Mariano Francesco Caratozzolo ◽

Graziano Pesole ◽

Elisabetta Sbisà ◽

Apollonia Tullo

Keyword(s):

Colorectal Cancer ◽

Clinical Practice ◽

Therapeutic Target ◽

Malignant Tumors ◽

Premature Death ◽

Chemotherapy Response ◽

Protein Levels ◽

Promising Therapeutic Target ◽

Trim Proteins

Colorectal cancer (CRC) represents one of the most widespread forms of cancer in the population and, as all malignant tumors, often develops resistance to chemotherapies with consequent tumor growth and spreading leading to the patient’s premature death. For this reason, a great challenge is to identify new therapeutic targets, able to restore the drugs sensitivity of cancer cells. In this review, we discuss the role of TRIpartite Motifs (TRIM) proteins in cancers and in CRC chemoresistance, focusing on the tumor-suppressor role of TRIM8 protein in the reactivation of the CRC cells sensitivity to drugs currently used in the clinical practice. Since the restoration of TRIM8 protein levels in CRC cells recovers chemotherapy response, it may represent a new promising therapeutic target in the treatment of CRC.

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