scholarly journals The Effects of Histone Deacetylase (HDAC) Inhibitors on FASN Intracellular Localization in Cancer Cells

2020 ◽  
Vol 21 (2) ◽  
Author(s):  
Elizabeth Colvin ◽  
Daiqing Liao
Keyword(s):  
Cell Proliferation ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Cancer Biology ◽  
Lipid Production ◽  
Intracellular Localization ◽  
Lipid Synthesis ◽  
Intracellular Location ◽  
The Impact

Understanding mechanisms underlying cancer biology is crucial for discovering novel and effective therapies to improve patient outcome. Increased lipid production is a major metabolic feature in cancer. The fatty acid synthase (FASN) is a key enzyme for lipid synthesis and is upregulated in cancer. Although fatty acid synthesis is generally thought to take place in the cytoplasm, it has been reported that this enzyme also localizes to the nucleus in cancer cells. We hypothesize that the intracellular localization FASN could be a potential target to decrease lipid synthesis and ultimately halt cell proliferation. Protein acetylation has been shown to regulate protein intracellular localization. We aim to assess the impact histone deacetylase inhibitors (HDACi) have on the intracellular location of FASN with the goal of reducing de novo lipid production and cancer cell proliferation. We have examined intracellular localization of FASN in cells using immunofluorescence microscopy in cancer cells treated with HDACi and did not detect obvious HDACi-induced changes in FASN localization. FASN is also regulated by other mechanisms such as phosphorylation. Future studies will examine effects of kinase inhibitors on FASN intracellular localization.

scholarly journals Survivin drives tumor-associated macrophage reprogramming: a novel mechanism with potential impact for obesity

2021 ◽  
Author(s):  
E. Benaiges ◽  
V. Ceperuelo-Mallafré ◽  
A. Madeira ◽  
R. Bosch ◽  
C. Núñez-Roa ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Expression Patterns ◽  
Intracellular Localization ◽  
Immunohistochemical Analysis ◽  
Subcellular Fractionation ◽  
Migration And Invasion ◽  
Macrophage Phenotype ◽  
Tumor Associated Macrophages ◽  
Obesity And Cancer ◽  
The Impact

Abstract Purpose Recent studies point to adipose-derived stem cells (ASCs) as a link between obesity and cancer. We aimed to determine whether survivin, which is highly secreted by ASCs from subjects with obesity, might drive a pro-tumoral phenotype in macrophages. Methods The effect of ASC conditioned medium on the macrophage phenotype was assessed by expression studies. Survivin intracellular localization and internalization were examined by subcellular fractionation and immunofluorescence, respectively. Loss- and gain-of-function studies were performed using adenoviral vectors, and gene expression patterns, migration and invasion capacities of cancer cells were examined. Heterotypic cultures of ASCs, macrophages and cancer cells were established to mimic the tumor microenvironment. Survivin-blocking experiments were used to determine the impact of survivin on both macrophages and cancer cells. Immunohistochemical analysis of survivin was performed in macrophages from ascitic fluids of cancer patients and healthy controls. Results We found that obese-derived ASCs induced a phenotypic switch in macrophages characterized by the expression of both pro- and anti-inflammatory markers. Macrophages were found to internalize extracellular survivin, generating hybrid macrophages with a tumor-associated phenotype that included secretion of survivin. Exogenous expression of survivin in macrophages generated a similar phenotype and enhanced the malignant characteristics of cancer cells by a mechanism dependent on survivin phosphorylation at threonine 34. Survivin secreted by both ASCs from subjects with obesity and tumor-associated macrophages synergistically boosted the malignancy of cancer cells. Importantly, survivin was mainly detected in ascites-associated macrophages from patients with a malignant diagnosis. Conclusion Our data indicate that survivin may serve as a molecular link between obesity and cancer and as a novel marker for tumor-associated macrophages.

scholarly journals Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis

2020 ◽  
Vol 8 (1) ◽  
pp. e000195 ◽  
Author(s):  
Johannes Laengle ◽  
Julijan Kabiljo ◽  
Leah Hunter ◽  
Jakob Homola ◽  
Sophie Prodinger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Valproic Acid ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Breast Cancer Cells ◽  
Histone Deacetylase Inhibitors ◽  
Combined Treatment ◽  
Dependent Cell ◽  
The Impact

BackgroundThe monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized.MethodsWe analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach.ResultsVPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the “do not eat me” signal CD47 on tumor cells.ConclusionsHDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.

scholarly journals RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaomeng Zhang ◽  
Ningyi Ma ◽  
Weiqiang Yao ◽  
Shuo Li ◽  
Zhigang Ren
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Overall Survival ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Aerobic Glycolysis ◽  
Cell Counting ◽  
Survival Prediction ◽  
Pancreatic Cancer Cells ◽  
The Impact

Abstract Background The DNA damage and repair pathway is considered a promising target for developing strategies against cancer. RAD51, also known as RECA, is a recombinase that performs the critical step in homologous recombination. RAD51 has recently received considerable attention due to its function in tumor progression and its decisive role in tumor resistance to chemotherapy. However, its role in pancreatic cancer has seldom been investigated. In this report, we provide evidence that RAD51, regulated by KRAS, promotes pancreatic cancer cell proliferation. Furthermore, RAD51 regulated aerobic glycolysis by targeting hypoxia inducible factor 1α (HIF1α). Methods TCGA (The Cancer Genome Atlas) dataset analysis was used to examine the impact of RAD51 expression on overall survival of pancreatic cancer patients. Lentivirus-mediated transduction was used to silence RAD51 and KRAS expression. Quantitative real-time PCR and western blot analysis validated the efficacy of the knockdown effect. Analysis of the glycolysis process in pancreatic cancer cells was also performed. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. Results Pancreatic cancer patients with higher levels of RAD51 exhibited worse survival. In pancreatic cancer cells, RAD51 positively regulated cell proliferation, decreased intracellular reactive oxygen species (ROS) production and increased the HIF1α protein level. KRAS/MEK/ERK activation increased RAD51 expression. In addition, RAD51 was a positive regulator of aerobic glycolysis. Conclusion The present study reveals novel roles for RAD51 in pancreatic cancer that are associated with overall survival prediction, possibly through a mechanism involving regulation of aerobic glycolysis. These findings may provide new predictive and treatment targets for pancreatic cancer.

scholarly journals Impact of Alternative Splicing Variants on Liver Cancer Biology

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 18
Author(s):  
Jose J. G. Marin ◽  
Maria Reviejo ◽  
Meraris Soto ◽  
Elisa Lozano ◽  
Maitane Asensio ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Survival Rates ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Splicing Variants ◽  
Mrna Maturation ◽  
Available Information ◽  
The Impact

The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

Histone Deacetylase Inhibitor Trichostatin A Suppresses Cell Proliferation and Induces Apoptosis by Regulating the PI3K/AKT Signalling Pathway in Gastric Cancer Cells

2020 ◽  
Vol 20 (17) ◽  
pp. 2114-2124
Author(s):  
Xinli An ◽  
Zekun Wei ◽  
Botian Ran ◽  
Hao Tian ◽  
Hongyu Gu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Flow Cytometry ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Trichostatin A ◽  
Gastric Cancer Cells ◽  
Growth Modulation ◽  
Regulatory Pathways

Background: Gastric cancer, a common malignant tumour worldwide, has a relatively poor prognosis and is a serious threat to human health. Histone Deacetylase Inhibitors (HDACi) are anticancer agents that are known to affect the cell growth of different cancer types. Trichostatin A (TSA) selectively inhibits the class I and II mammalian Histone Deacetylase (HDAC) family enzymes and regulates many cell processes. Still, the underlying mechanisms of HDACs are not fully understood in gastric cancer. Objective: This study aims to investigate the antitumor effect and the mechanism of growth modulation of gastric cancer cells by TSA. Methods: The cell proliferation of gastric cancer cells was measured by MTT and BrdU immunofluorescence assays. Soft agar assay was used to detect the colony formation ability of gastric cancer cells. Flow cytometry was used to examine cell cycle and apoptosis. Western blot was employed to detect protein expression of target factors. Results: TSA inhibits the proliferation of MKN-45 and SGC-7901 cells and leads to significant repression of colony number and size. Flow cytometry assays show TSA induces cell cycle arrest at G1 phase and apoptosis, and TSA effects the expression of related factors in the mitochondrial apoptotic signalling and cell cycle-related regulatory pathways. Furthermore, TSA increased histone H3K27 acetylation and downregulated the expression of PI3K and p-AKT. Conclusion: Downregulating PI3K/AKT pathway activation is involved in TSA-mediated proliferation inhibition of gastric cancer.

scholarly journals DNA licensing as a novel androgen receptor mediated therapeutic target for prostate cancer

2009 ◽  
Vol 16 (2) ◽  
pp. 325-332 ◽  
Author(s):  
Jason M D'Antonio ◽  
Donald J Vander Griend ◽  
John T Isaacs
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Dna Replication ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Prostate Cancer Cells ◽  
Normal Prostate ◽  
Malignant Prostate

During middle G1 of the cell cycle origins of replication orchestrate the ordered assembly of the pre-replication complex (pre-RC), allowing licensing of DNA required for DNA replication. Cyclin-dependent kinase activation of the pre-RC facilitates the recruitment of additional signaling factors, which triggers DNA unwinding and replication, while limiting such DNA replication to once and only once per cell cycle. For both the normal and malignant prostate, androgen is the major stimulator of cell proliferation and thus DNA replication. In both cases, the binding of androgen to the androgen receptor (AR) is required. However, the biochemical cascade involved in such AR-stimulated cell proliferation and DNA synthesis is dramatically different in normal versus malignant prostate cells. In normal prostate, AR-stimulated stromal cell paracrine secretion of andromedins stimulates DNA replication within prostatic epithelial cells, in which AR functions as a tumor suppressor gene by inducing proliferative quiescence and terminal differentiation. By direct contrast, nuclear AR in prostate cancer cells autonomously stimulates continuous growth via incorporation of AR into the pre-RC. Such a gain of function by AR-expressing prostate cancer cells requires that AR be efficiently degraded during mitosis since lack of such degradation leads to re-licensing problems, resulting in S-phase arrest during the subsequent cell cycle. Thus, acquisition of AR as part of the licensing complex for DNA replication represents a paradigm shift in how we view the role of AR in prostate cancer biology, and introduces a novel vulnerability in AR-expressing prostate cancer cells apt for therapeutic intervention.

scholarly journals LncRNA SLC7A11-AS1 is Upregulated in Colorectal Cancer and Promotes the Proliferation of Cancer Cells by Suppressing the Maturation of miR-34a

2021 ◽  
Author(s):  
Peijiang Chang ◽  
Maosheng Wang
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Prognostic Value ◽  
Inhibitory Effects ◽  
Poor Survival ◽  
Tumor Tissues ◽  
Tcga Dataset

Abstract Background: LncRNA SLC7A11-AS1 is recently characterized critical player in cancer biology. We analyzed TCGA dataset and observed the upregulation of SLC7A11-AS1 in colorectal cancer (CRC). We therefore analyzed the role of SLC7A11-AS1 in CRC. Methods: Paired CRC and non-tumor tissues were collected from 60 CRC patients and expression of SLC7A11-AS1 in tissues was determined by RT-qPCR. The 60 CRC patients were followed up for 5 years to analyze the prognostic value of SLC7A11-AS1 for CRC. Correlations were analyzed by linear regression. The effects of SLC7A11-AS1 overexpression on the expression of miR-34a precursor and mature miR-34a were analyzed by RT-qPCR. Cell proliferation was analyzed by CCK-8 assay.Result: SLC7A11-AS1 was upregulated in CRC and predicted poor survival. SLC7A11-AS1 and mature miR-34a were inversely correlated, while SLC7A11-AS1 was not significantly correlated with the precursor of miR-34a. In CRC cells, SLC7A11-AS1 overexpression resulted in the reduced level of mature miR-34a, but not miR-34a precursor. Moreover, SLC7A11-AS1 overexpression reduced the inhibitory effects of miR-34a overexpression on cell proliferation. Conclusion: SLC7A11-AS1 may promote the proliferation of cancer cells in CRC by suppressing the maturation of miR-34a.

scholarly journals Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 148 ◽  
Author(s):  
Anna Wawruszak ◽  
Joanna Kalafut ◽  
Estera Okon ◽  
Jakub Czapinski ◽  
Marta Halasa ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hematological Malignancies ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Clinical Disorders ◽  
The Impact

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.

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