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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10990/802

Autori: Mio, Catia
Supervisore afferente all'Università: DI LORETO, CARLA
Titolo: Analysis of the biological mechanisms de-regulated after pharmacological BET inhibition in a model of anaplastic thyroid cancer
Abstract (in inglese): In the portrait of epigenetic anti-cancer drugs, BET inhibitors (BETi) represent an appealing innovative class of compounds. They target the Bromodomain and Extra-Terminal (BET) proteins that act as regulators of gene transcription due to the interaction with histone acetyl groups. BETi are known to affect multiple biological pathways. The aim of this study is to outline which are the chief pathways underlying the biological effects derived from BET inhibition, in order to better understand their anti-neoplastic potential. To pursue this aim, anaplastic thyroid carcinoma (ATC)-derived cell lines were used as a model of highly aggressive cancer subtype. The effects of BET inhibition were evaluated in terms of different biological outputs, in diverse ATC cell lines (FRO, SW1736 and 8505c). The treatment with different BETi (JQ1, I-BET762 and I-BET151) decreased cell viability, increased the proportion of cells stacked in G0-G1 cell cycle phases and determined an increase in cell death phenomena. In order to find BETi effectors, a global transcriptome analysis was performed after JQ1 treatment. RNA-seq data highlighted a significant deregulation of cell cycle regulators. Among them, MCM5 was down-regulated at both mRNA and protein levels in all tested cell lines. Furthermore, ChIP experiments indicated that MCM5 is a direct target of BRD4. MCM5 silencing reduced ATC cell proliferation in an analogous way as JQ1 treatment, thus underlining its connection in the block of proliferation induced by BETi. Moreover, JQ1 treatment reduced Mcm5 mRNA expression in two murine ATC-derived cell lines. Thus, these data proved that, through MCM5, BET inhibition directly affects cell cycle progression. Nowadays, many reports showed that miRNAs are key elements in the regulation of several biological processes and that, if deregulated, could contribute to several diseases, including cancer. Hitherto, data concerning the relationship between BET inhibition and miRNA expression are very scanty. Therefore, a second goal of this study was to delineate if BET inhibitors could regulate miRNA expression in ATC cells. JQ1 treatment altered the expression of several miRNAs, 7 of which turned out to be commonly deregulated in ATC cells after both 48h and 72h treatments in two cell lines. An algorithm was applied to enlist the putative miRNA-associated target genes of this pool. These targets have been, then, subjected to gene ontology analysis, in order to outline the biological pathways in which these miRNAs are involved. It has been assessed a strong enrichment in the STAT3 and PTEN signal transduction pathways, which was confirmed by detecting an up-regulation of PTEN, p21 and p27 levels. A subgroup of miRNAs (hsa-miR-4516, hsa-miR-1234, hsa-miR-4488) turned out to be down-regulated in ATC cell lines, when compared to the non-tumorigenic ones (NThy ori 3.1), and interestingly JQ1 treatment in ATC cells induced the up-regulation of these miRNAs, restoring, in some way, their expression levels. Thus, these data hypothesized that modulation of miRNA expression is one of the multiple mechanisms of BETi action in thyroid cancer cells. Taken together, these data highlighted the multi-target output due to BET inhibition. Moreover, they suggest a possible usage of BET inhibitors in the management of anaplastic thyroid cancer. However, further investigations are needed to have a better insight on the multiple targets of these pharmacological inhibitors.
Parole chiave: Epigenetics; BET inhibitors; Thyroid cancer
MIUR : Settore MED/08 - Anatomia Patologica
Lingua: eng
Data: 29-mar-2017
Corso di dottorato: Dottorato di ricerca in Medicina cellulare e molecolare
Ciclo di dottorato: 29
Università di conseguimento titolo: Università degli Studi di Udine
Luogo di discussione: Udine
Altre informazioni: Co-supervisore: Giuseppe Damante
Citazione: Mio, C. Analysis of the biological mechanisms de-regulated after pharmacological BET inhibition in a model of anaplastic thyroid cancer. (Doctoral Thesis, Università degli Studi di Udine, 2017).
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