Epigenetic changes promoting HeLa cell apoptosis are linked to valproic acid-induced down-regulation of REST and its corepressor CoREST

Khodeneva, Natalya (2016) Epigenetic changes promoting HeLa cell apoptosis are linked to valproic acid-induced down-regulation of REST and its corepressor CoREST, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biochimiche e biotecnologiche, 28 Ciclo. DOI 10.6092/unibo/amsdottorato/7651.
Documenti full-text disponibili:
[img]
Anteprima
Documento PDF (English) - Richiede un lettore di PDF come Xpdf o Adobe Acrobat Reader
Download (3MB) | Anteprima

Abstract

REST (RE-1 silencing transcription factor, or NRSF –neuron-restrictive silencing factor) binds to a conserved RE-1 motif present in the promoter region of regulated genes and represses their transcription in neuronal and non-neuronal cells (Bruce et al., 2004). REST recruits corepressors (CoREST, mSin3a) and multiple chromatin modifying enzymes (HDAC1/2, demethylase LSD1 and methyltransferase G9a), causing chromatin compaction and altering gene expression by changing epigenetic tagets (Ballas et al., 2005). REST contributes to orchestrate the epigenetic regulation of target genes through several miRNAs including miR-9/9*, miR-29a, miR-124a, miR-218 and others (Wu and Xie, 2006). My thesis has ascertained an anti-tumor properties of transcription factor REST on a model of cervical adenocarcinoma where class I histone deacetylase (HDAC) inhibitor: valproic acid (VPA) down-regulates REST and its corepressors CoREST and HDAC1 at mRNA and protein level. These effects are related to a potent effect on cell apoptosis, possibly mediated by miR-9 overexpression as consequence of REST and CoREST down-regulation. I report the presence of a double-negative feedback loop between REST and miR-9 in HeLa cell line: in absence of REST, miR-9 levels substantially increase while miR-9 overexpression promotes REST down-regulation. Interestingly, I have observed that REST is sufficient to induce a noteworthy chromatin remodeling in HeLa cells. HeLa cell apoptosis induced by these events, involves mitochondrial control of apoptosis signaling pathways, particularly Bcl-2 family gene BAX. In conclusion, the present study aims to contribute to a more accurate comprehension of the processes responsible for REST activity in a model of epithelial cervical adenocarcinoma, and relevant for a detailed knowledge of important events causing oncogenesis. Moreover, considering the crucial role of epigenetic regulation of gene transcription in the etiology of many pathological conditions, any further knowledge in this field could find important and innovative pharmacological applications.

Abstract
Tipologia del documento
Tesi di dottorato
Autore
Khodeneva, Natalya
Supervisore
Dottorato di ricerca
Scuola di dottorato
Scienze biologiche, biomediche e biotecnologiche
Ciclo
28
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
REST, CoREST, VPA, microRNA, epigenetics, cervical cancer, apoptosis
URN:NBN
DOI
10.6092/unibo/amsdottorato/7651
Data di discussione
3 Maggio 2016
URI

Altri metadati

Statistica sui download

Gestione del documento: Visualizza la tesi

^