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Stephen Safe, James L Abbruzzese, Maen Abdelrahim, Erik Hedrick
Specificity protein (Sp) transcription factors (TFs) such as Sp1 are critical for early development but their expression decreases with age and there is evidence that transformation of normal cells to cancer cells is associated with upregulation of Sp1, Sp3 and Sp4 which are highly expressed in cancer cells and tumors. Sp1 is a negative prognostic factor for pancreatic, colon, glioma, gastric, breast, prostate, and lung cancer patients. Functional studies also demonstrate that Sp TFs regulate genes responsible for cancer cell growth, survival, migration/invasion, inflammation and drug resistance, and Sp1, Sp3 and Sp4 are also non-oncogene addiction (NOA) genes and important drug targets...
March 15, 2018: Cancer Prevention Research
Sinae Kim, Eunji Lee, Jaeyun Jung, Jong Won Lee, Hee Jung Kim, Jisun Kim, Hyun Ju Yoo, Hee Jin Lee, Sun Young Chae, Sang Min Jeon, Byung Ho Son, Gyungyup Gong, Shyam K Sharan, Suhwan Chang
MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various biological processes including tumorigenesis. Here, we addressed the function of miR-155 using LC-MS/MS-based metabolic profiling of miR-155 deficient breast cancer cells. Our results revealed the loss of miR-155 hampers glucose uptake and glycolysis, via the down-regulation of glucose transporters and metabolic enzymes including HK2, PKM2, and LDHA. We showed this is due to the down-regulation of cMYC, controlled through phosphoinositide-3-kinase regulatory subunit alpha (PIK3R1)-PDK1/AKT-FOXO3a pathway...
March 12, 2018: Oncogene
Hang-Soo Park, Hyosung Kwon, Jewon Yu, Yeonju Bae, Jae-Yong Park, Kyung-Ah Choi, Yeonho Choi, Sunghoi Hong
Direct conversion is a powerful approach to safely generate mature neural lineages with potential for treatment of neurological disorders. Astrocytes play a crucial role in neuronal homeostasis and their dysfunctions contribute to several neurodegenerative diseases. Using a single-cell approach for precision, we describe here a robust method using optimized DNA amounts for the direct conversion of mouse fibroblasts to astrocytes. Controlled amount of the reprogramming factors Oct4, Sox2, Klf4 and cMyc was directly delivered into a single fibroblast cell...
March 6, 2018: Artificial Cells, Nanomedicine, and Biotechnology
María Del Carmen Ortuño-Costela, Ana Moreno-Izquierdo, Rafael Garesse, M Esther Gallardo
We have generated a human iPSC line, IISHDOi002-A, from commercial primary normal human dermal fibroblasts belonging to an African mitochondrial haplogroup (L3), and with a 46, XY/47, XYY mosaicism. For this purpose, reprogramming factors Oct3/4, Sox2, Klf4 and cMyc were delivered using a non-integrative methodology that involves the use of Sendai virus.
February 14, 2018: Stem Cell Research
Santosh K Misra, Taylor L Kampert, Dipanjan Pan
Pathogenesis of many cancer is driven by the Myc oncoprotein, its dimerization with Max, and the binding of this heterodimer to E-Boxes of target genes. The systemic effectiveness of potent small molecule inhibitors of Myc-Max dimerization has been lim-ited by poor bioavailability, rapid metabolism, and inadequate target site penetration. The potential of gene therapy for target-ing Myc can be fully realized by successful synthesis of a smart cargo. We developed a 'nuclein' type nanoparticle "siNozyme" (45±5 nm) from nano-assembly of pamitoyl-bio-conjugated acetyl co-enzyme-A for stable incorporation of chemotherapeutics and biologics to achieve remarkable growth inhibition of human melanoma...
February 21, 2018: Bioconjugate Chemistry
Arantxa Bolinches-Amorós, Dunja Lukovic, Ana Artero Castro, Marian León Rodriguez, Kunka Kamenarova, Radka Kaneva, Pavla Jendelova, Fiona Blanco-Kelly, Carmen Ayuso, Marta Cortón, Slaven Erceg
The human iPSC cell line, GLC-FiPS4F1 (ESi047-A), derived from dermal fibroblast from the patient with congenital glaucoma caused by the mutation of the gene CYP1B1, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors.
January 4, 2018: Stem Cell Research
Veronica D Gonzalez, Nikolay Samusik, Tiffany J Chen, Erica S Savig, Nima Aghaeepour, David A Quigley, Ying-Wen Huang, Valeria Giangarrà, Alexander D Borowsky, Neil E Hubbard, Shih-Yu Chen, Guojun Han, Alan Ashworth, Thomas J Kipps, Jonathan S Berek, Garry P Nolan, Wendy J Fantl
We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses...
February 13, 2018: Cell Reports
Abraham Neelankal John, Fang-Xu Jiang
One significant health issue that plagues contemporary society is that of Type 2 diabetes (T2D). This disease is characterised by higher-than-average blood glucose levels as a result of a combination of insulin resistance and insufficient insulin secretions from the β-cells of pancreatic islets of Langerhans. Previous developmental research into the pancreas has identified how early precursor genes of pancreatic β-cells, such as Cpal, Ngn3, NeuroD, Ptf1a, and cMyc, play an essential role in the differentiation of these cells...
December 14, 2017: Journal of Diabetes and its Complications
Juan Roberto Rodriguez-Madoz, Edurne San Jose-Eneriz, Obdulia Rabal, Natalia Zapata-Linares, Estibaliz Miranda, Saray Rodriguez, Angelo Porciuncula, Amaia Vilas-Zornoza, Leire Garate, Victor Segura, Elizabeth Guruceaga, Xabier Agirre, Julen Oyarzabal, Felipe Prosper
The combination of defined factors with small molecules targeting epigenetic factors is a strategy that has been shown to enhance optimal derivation of iPSCs and could be used for disease modelling, high throughput screenings and/or regenerative medicine applications. In this study, we showed that a new first-in-class reversible dual G9a/DNMT1 inhibitor compound (CM272) improves the efficiency of human cell reprogramming and iPSC generation from primary cells of healthy donors and patient samples, using both integrative and non-integrative methods...
2017: PloS One
Li Wang, Evangelia Koutelou, Calley Hirsch, Ryan McCarthy, Andria Schibler, Kevin Lin, Yue Lu, Collene Jeter, Jianjun Shen, Michelle C Barton, Sharon Y R Dent
Precise control of gene expression during development is orchestrated by transcription factors and co-regulators including chromatin modifiers. How particular chromatin-modifying enzymes affect specific developmental processes is not well defined. Here, we report that GCN5, a histone acetyltransferase essential for embryonic development, is required for proper expression of multiple genes encoding components of the fibroblast growth factor (FGF) signaling pathway in early embryoid bodies (EBs). Gcn5-/- EBs display deficient activation of ERK and p38, mislocalization of cytoskeletal components, and compromised capacity to differentiate toward mesodermal lineage...
December 12, 2017: Stem Cell Reports
Loana Musso, Stefania Mazzini, Anna Rossini, Lorenzo Castagnoli, Leonardo Scaglioni, Roberto Artali, Massimo Di Nicola, Franco Zunino, Sabrina Dallavalle
BACKGROUND: Pyridoquinazolinecarboxamides have been reported as RNA polymerase I inhibitors and represent a novel class of potential antitumor agents. BMH-21, was reported to intercalate with GC-rich rDNA, resulting in nucleolar stress as a primary mechanism of cytotoxicity. METHODS: The interaction of BMH-21 and analogues with DNA G-quadruplex structures was studied by NMR and molecular modelling. The cellular response was investigated in a panel of human tumor cell lines and protein expression was examined by Western Blot analysis...
March 2018: Biochimica et Biophysica Acta
Ying-Chun Shen, Ali Ghasemzadeh, Christina M Kochel, Thomas R Nirschl, Brian J Francica, Zoila A Lopez-Bujanda, Maria A Carrera Haro, Ada Tam, Robert A Anders, Mark J Selby, Alan J Korman, Charles G Drake
BACKGROUND: Immune checkpoint blockade has shown promising antitumor activity against a variety of tumor types. However, responses in castration-resistant prostate cancer remain relatively rare-potentially due to low baseline levels of infiltration. Using an immunocompetent cMyc-driven model (Myc-CaP), we sought to understand the immune infiltrate induced by androgen deprivation therapy (ADT) and to leverage that infiltration toward therapeutic benefit. METHODS: Using flow cytometry, qPCR and IHC, we quantified ADT-induced immune infiltration in terms of cell type and function...
December 4, 2017: Prostate Cancer and Prostatic Diseases
Atul Anand, Calvin Chin, Anoop S V Shah, Jacek KwieciÅ Ski, Alex Vesey, Joanna Cowell, Ekkehard Weber, Thomas Kaier, David E Newby, Marc Dweck, Michael S Marber, Nicholas L Mills
OBJECTIVE: Cardiac myosin-binding protein C (cMyC) is an abundant sarcomeric protein and novel highly specific marker of myocardial injury. Myocyte death characterises the transition from hypertrophy to replacement myocardial fibrosis in advanced aortic stenosis. We hypothesised that serum cMyC concentrations would be associated with cardiac structure and outcomes in patients with aortic stenosis. METHODS: cMyC was measured in two cohorts in which serum had previously been prospectively collected: a mechanism cohort of patients with aortic stenosis (n=161) and healthy controls (n=46) who underwent cardiac MRI, and an outcome cohort with aortic stenosis (n=104) followed for a median of 11...
December 1, 2017: Heart: Official Journal of the British Cardiac Society
Dan-Dan Xu, Xiao-Feng Li, Yu-Huan Li, Yan-Hui Liu, Cheng Huang, Xiao-Ming Meng, Jun Li
TIPE2, the tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TNFAIP8L2), plays an important role in regulating inflammation and immune homeostasis. Recent studies discovered that TIPE-2 involved in the development of several tumors and other proliferative diseases. The purpose of this study was to explore the function of TIPE-2 in the activation and proliferation in HSC-T6 cells. Our study showed low expression of TIPE-2 in primary HSCs from CCl4-treated mice and activated HSC-T6 cells. Functionally, over-expression of TIPE-2 by GV141-TIPE-2 hindered the HSC-T6 cells activation and proliferation and expressions of β-Catenin, Cmyc, Cyclin D1...
November 28, 2017: Biochemical and Biophysical Research Communications
Pragyaparamita Sahoo, Soumya Ranjan Jena, Luna Samanta
Currently Cancer is the leading cause of death worldwide. Malignancy or cancer is a class of diseases characterized by uncontrolled cell growth that eventually invade other tissues and dvelop secondary malignant growth at other sites by metastasis. Intercellular communication plays a major in cancer, particularly in the process of cell proliferation and coordination which in turn leads to tumor invasion, metastasis and development of resistance to therapy. Cells communicate among themselves in a variety of ways, namely, i) via gap junctions with adjacent cells, ii) via exosomes with nearby cells and iii) via chemical messengers with distant cells...
November 29, 2017: Current Cancer Drug Targets
Cheng Liu, Wei-Chang Lee, Bu-Miin Huang, Yi-Chen Chia, Yu-Chi Chen, Yung-Chia Chen
BACKGROUND: Renal cell carcinoma (RCC) is well known that it cannot be treated with traditional chemotherapy or radiotherapy. 16-Hydroxycleroda-3,13-dien-15,16-olide (CD), isolated from Polyalthia longifolia Benth. & Hook. f. var. pendula had been reported to display significant efficacy against cancer cell lines. PURPOSE: To determine the anti-tumour activities of CD in two clear cell type RCC (ccRCC) cell lines (A-498 and 786-O). In addition, the underlying mechanisms were also examined...
December 1, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Marieke Aarts, Athena Georgilis, Meryam Beniazza, Patrizia Beolchi, Ana Banito, Thomas Carroll, Marizela Kulisic, Daniel F Kaemena, Gopuraja Dharmalingam, Nadine Martin, Wolf Reik, Johannes Zuber, Keisuke Kaji, Tamir Chandra, Jesús Gil
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates...
October 15, 2017: Genes & Development
Michael Daniel, Trygve O Tollefsbol
Human telomerase reverse transcriptase (hTERT) encodes the catalytic subunit of telomerase, which has been shown to be upregulated in many cancers. Pterostilbene is a naturally occurring stilbenoid and phytoalexin found primarily in blueberries that exhibits antioxidant activity and inhibits the growth of various cancer cell types. Therefore, the aim of this study was to determine whether treatment with pterostilbene, at physiologically achievable concentrations, can inhibit the proliferation of breast cancer cells and down-regulate the expression of hTERT...
November 10, 2017: Journal of Cellular Biochemistry
Christina M Albanese, Suttipong Suttapitugsakul, Shruthi Perati, Linda B McGown
Limitations of Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and related methods that depend upon combinatorial oligonucleotide libraries have hindered progress in this area. Our laboratory has introduced a new approach to aptamer discovery that uses oligonucleotides with sequences drawn from the human genome to capture proteins from biological samples. Specifically, we have focused on capture of proteins in nuclear extracts from human cell lines using G-quadruplex (G4) forming genomic sequences...
January 15, 2018: Talanta
Xiaoyun Liu, Wei Wei, Wenjun Zhu, Lufang Su, Zeyang Xiong, Man Zhou, Yu Zheng, Dao-Xiu Zhou
How plant metabolic flux alters gene expression to optimize plant growth and response to stress remains largely unclear. Here, we report that Arabidopsis thaliana NAD+ -dependent histone deacetylase AtSRT1 negatively regulates plant tolerance to stress and glycolysis but stimulates mitochondrial respiration. We found that AtSRT1 interacts with Arabidopsis cMyc-Binding Protein 1 (AtMBP-1), a transcriptional repressor produced by alternative translation of the cytosolic glycolytic enolase gene LOS2/ENO2. We demonstrated that AtSRT1 could associate with the chromatin of AtMBP-1 targets LOS2/ENO2 and STZ/ZAT10, both of which encode key stress regulators, and reduce the H3K9ac levels at these genes to repress their transcription...
December 4, 2017: Molecular Plant
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