Emanuela Chiarella

Bio: Emanuela Chiarella is an academic researcher from Magna Græcia University. The author has contributed to research in topics: Haematopoiesis & Stem cell. The author has an hindex of 12, co-authored 26 publications receiving 327 citations.

Ferritin heavy chain is a negative regulator of ovarian cancer stem cell expansion and epithelial to mesenchymal transition

Abstract: // Nadia Lobello 1, * , Flavia Biamonte 1, * , Maria Elena Pisanu 2, 3 , Maria Concetta Faniello 1 , Žiga Jakopin 4 , Emanuela Chiarella 5 , Emilia Dora Giovannone 5, 6 , Rita Mancini 2, 3 , Gennaro Ciliberto 7 , Giovanni Cuda 1, * , Francesco Costanzo 1, * 1 Centro di Ricerca di Biochimica e Biologia Molecolare Avanzata, Dipartimento di Medicina Sperimentale e Clinica, Universita degli Studi “Magna Graecia”, Catanzaro, Italy 2 Dipartimento di Medicina Clinica e Molecolare, Sapienza Universita di Roma, Italy 3 Laboratorio di Biologia Cellulare e Molecolare, Dipartimento di Chirurgia “P. Valdoni”, Sapienza Universita di Roma, Italy 4 Faculty of Pharmacy, University of Ljubljana, Slovenia 5 Dipartimento di Medicina Sperimentale e Clinica, Universita degli Studi “Magna Graecia”, Catanzaro, Italy 6 Centro Interdipartimentale di Servizi e Ricerca, Universita degli Studi “Magna Graecia”, Catanzaro, Italy 7 Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione G. Pascale”, Napoli, Italy * These authors contributed equally to this work Correspondence to: Gennaro Ciliberto, email: g.ciliberto@istitutotumori.na.it Keywords: ferritin heavy chain, ovarian cancer, cancer stem cells, EMT, miRNAs Received: February 28, 2016 Accepted: August 09, 2016 Published: August 22, 2016 ABSTRACT Objectives: Ferritin is the major intracellular iron storage protein essential for maintaining the cellular redox status. In recent years ferritin heavy chain (FHC) has been shown to be involved also in the control of cancer cell growth. Analysis of public microarray databases in ovarian cancer revealed a correlation between low FHC expression levels and shorter survival. To better understand the role of FHC in cancer, we have silenced the FHC gene in SKOV3 cells. Results: FHC-KO significantly enhanced cell viability and induced a more aggressive behaviour. FHC-silenced cells showed increased ability to form 3D spheroids and enhanced expression of NANOG, OCT4, ALDH and Vimentin. These features were accompanied by augmented expression of SCD1, a major lipid metabolism enzyme. FHC apparently orchestrates part of these changes by regulating a network of miRNAs. Methods: FHC-silenced and control shScr SKOV3 cells were monitored for changes in proliferation, migration, ability to propagate as 3D spheroids and for the expression of stem cell and epithelial-to-mesenchymal-transition (EMT) markers. The expression of three miRNAs relevant to spheroid formation or EMT was assessed by q-PCR. Conclusions: In this paper we uncover a new function of FHC in the control of cancer stem cells.

Zinc finger protein 521 antagonizes early B-cell factor 1 and modulates the B-lymphoid differentiation of primary hematopoietic progenitors

Abstract: Zinc finger protein 521 (EHZF/ZNF521) is a multi-functional transcription co-factor containing 30 zinc fingers and an amino-terminal motif that binds to the nucleosome remodelling and histone deacetylase (NuRD) complex. ZNF521 is believed to be a relevant player in the regulation of the homeostasis of the hematopoietic stem/progenitor cell compartment, however the underlying molecular mechanisms are still largely unknown. Here, we show that this protein plays an important role in the control of B-cell development by inhibiting the activity of early B-cell factor-1 (EBF1), a master factor in B-lineage specification. In particular, our data demonstrate that: (1) ZNF521 binds to EBF1 via its carboxyl-terminal portion and this interaction is required for EBF1 inhibition; (2) NuRD complex recruitment by ZNF521 is not essential for the inhibition of transactivation of EBF1-dependent promoters; (3) ZNF521 represses EBF1 target genes in a human B-lymphoid molecular context; and (4) RNAi-mediated silencing of ZNF521/Zfp521 in primary human and murine hematopoietic progenitors strongly enhances the generation of B-lymphocytes in vitro. Taken together, our data indicate that ZNF521 can antagonize B-cell development and lend support to the notion that it may contribute to conserve the multipotency of primitive lympho-myeloid progenitors by preventing or delaying their EBF1-driven commitment toward the B-cell lineage.

Critical role of zinc finger protein 521 in the control of growth, clonogenicity and tumorigenic potential of medulloblastoma cells.

Abstract: // Raffaella Spina 1,3,7,* , Gessica Filocamo 2,* , Enrico Iaccino 1 , Stefania Scicchitano 1 , Michela Lupia 1 , Emanuela Chiarella 1 , Tiziana Mega 1 , Francesca Bernaudo 1 , Daniela Pelaggi 1 , Maria Mesuraca 1 , Simonetta Pazzaglia 4 , Samantha Semenkow 3 , Eli E. Bar 3,7 , Marcel Kool 5 , Stefan Pfister 5,6 , Heather M. Bond 1 , Charles G. Eberhart 3 , Christian Steinkuhler 2 , Giovanni Morrone 1 1 Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Dept. of Experimental and Clinical Medicine, University of Catanzaro Magna Graecia, Catanzaro, Italy. 2 Exiris srl, Via Castelfidardo 8, Rome, Italy. 3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore MD, USA. 4 Section of Toxicology and Biomedical Sciences, ENEA CR-Casaccia, Via Anguillarese 301, S.Maria di Galeria (Roma), Italy. 5 Division of Pediatric Neurooncology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany. 6 Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany 7 Current address: Department of Neurological Surgery, Case Western Reserve University, Cleveland, Ohio, USA. * These authors contributed equally to this work Correspondence: Giovanni Morrone, email: // Christian Steinkuhler, email: // Charles G. Eberhart, email: // Keywords : ZNF521; gene expression; medulloblastoma; cell growth; tumorigenicity; cancer stem cells. Received : July 14, 2013 Accepted : July 25, 2013 Published : July 27, 2013 Abstract The stem cell-associated transcription co-factor ZNF521 has been implicated in the control of hematopoietic, osteo-adipogenic and neural progenitor cells. ZNF521 is highly expressed in cerebellum and in particular in the neonatal external granule layer that contains candidate medulloblastoma cells-of-origin, and in the majority of human medulloblastomas. Here we have explored its involvement in the control of human and murine medulloblastoma cells. The effect of ZNF521 on growth and tumorigenic potential of human medulloblastoma cell lines as well as primary Ptc1 -/+ mouse medulloblastoma cells was investigated in a variety of in vitro and in vivo assays, by modulating its expression using lentiviral vectors carrying the ZNF521 cDNA, or shRNAs that silence its expression. Enforced overexpression of ZNF521 in DAOY medulloblastoma cells significantly increased their proliferation, growth as spheroids and ability to generate clones in single-cell cultures and semisolid media, and enhanced their migratory ability in wound-healing assays. Importantly, ZNF521-expressing cells displayed a greatly enhanced tumorigenic potential in nude mice. All these activities required the ZNF521 N-terminal motif that recruits the nucleosome remodeling and histone deacetylase complex, which might therefore represent an appealing therapeutic target. Conversely, silencing of ZNF521 in human UW228 medulloblastoma cells that display high baseline expression decreased their proliferation, clonogenicity, sphere formation and wound-healing ability. Similarly, Zfp521 silencing in mouse Ptc1 -/+ medulloblastoma cells drastically reduced their growth and tumorigenic potential. Our data strongly support the notion that ZNF521, through the recruitment of the NuRD complex, contributes to the clonogenic growth, migration and tumorigenicity of medulloblastoma cells.

Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death

Abstract: Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites of iron utilization and master regulators of oxidative metabolism, mitochondria are the main source of reactive oxygen species (ROS) and, thus, play a role in this type of RCD. Ferroptosis is, indeed, associated with severe damage in mitochondrial morphology, bioenergetics, and metabolism. Furthermore, dysregulation of mitochondrial metabolism is considered a biochemical feature of neurodegenerative diseases linked to ferroptosis. Whether mitochondrial dysfunction can, per se, initiate ferroptosis and whether mitochondrial function in ferroptosis is context-dependent are still under debate. Cancer cells accumulate high levels of iron and ROS to promote their metabolic activity and growth. Of note, cancer cell metabolic rewiring is often associated with acquired sensitivity to ferroptosis. This strongly suggests that ferroptosis may act as an adaptive response to metabolic imbalance and, thus, may constitute a new promising way to eradicate malignant cells. Here, we review the current literature on the role of mitochondria in ferroptosis, and we discuss opportunities to potentially use mitochondria-mediated ferroptosis as a new strategy for cancer therapy.

Regulation of early adipose commitment by Zfp521.

Abstract: While there has been significant progress in determining the transcriptional cascade involved in terminal adipocyte differentiation, less is known about early events leading to lineage commitment and cell fate choice. It has been recently discovered that zinc finger protein 423 (Zfp423) is an early actor in adipose determination. Here, we show that a close paralog of Zfp423, Zfp521, acts as a key regulator of adipose commitment and differentiation in vitro and in vivo. Zfp521 exerts its actions by binding to early B cell factor 1 (Ebf1), a transcription factor required for the generation of adipocyte progenitors, and inhibiting the expression of Zfp423. Overexpression of Zfp521 in cells greatly inhibits adipogenic potential, whereas RNAi-mediated knock-down or genetic ablation of Zfp521 enhances differentiation. In addition, Zfp521−/− embryos exhibit increased mass of interscapular brown adipose tissue and subcutaneous white adipocytes, a cell autonomous effect. Finally, Ebf1 participates in a negative feedback loop to repress Zfp521 as differentiation proceeds. Because Zfp521 is known to promote bone development, our results suggest that it acts as a critical switch in the commitment decision between the adipogenic and osteogenic lineages.

The regulatory network of B-cell differentiation: a focused view of early B-cell factor 1 function.

Abstract: During the last decades, many studies have investigated the transcriptional and epigenetic regulation of lineage decision in the hematopoietic system. These efforts led to a model in which extrinsic signals and intrinsic cues establish a permissive chromatin context upon which a regulatory network of transcription factors and epigenetic modifiers act to guide the differentiation of hematopoietic lineages. These networks include lineage-specific factors that further modify the epigenetic landscape and promote the generation of specific cell types. The process of B lymphopoiesis requires a set of transcription factors, including Ikaros, PU.1, E2A, and FoxO1 to ‘prime’ cis-regulatory regions for subsequent activation by the B-lineage-specific transcription factors EBF1 and Pax-5. The expression of EBF1 is initiated by the combined action of E2A and FoxO1, and it is further enhanced and maintained by several positive feedback loops that include Pax-5 and IL-7 signaling. EBF1 acts in concert with Ikaros, PU.1, Runx1, E2A, FoxO1, and Pax-5 to establish the B cell-specific transcription profile. EBF1 and Pax-5 also collaborate to repress alternative cell fates and lock cells into the B-lineage fate. In addition to the functions of EBF1 in establishing and maintaining B-cell identity, EBF1 is required to coordinate differentiation with cell proliferation and survival.