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Filippi, Letizia (2018) Epigenetic Control of YAP/TAZ-Mediated Transcription. [Ph.D. thesis]

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Abstract (italian or english)

An emerging paradigm in cancer biology relates to the concept of "transcriptional addiction" where transformed cells set high demand of general transcriptional regulators, chromatin modifiers and even the basal transcriptional machinery to sustain a dysregulated gene expression program. The mechanism and the players below these dependencies remained elusive. Identifying the most sensitive nodes of these regulations offers the potential of defining new targets and therapeutics with selective antitumor effects. Here we demonstrate that the two closely related transcriptional co-activator YAP and TAZ mediate transcriptional dependencies in different cellular contexts.
They are known to be aberrantly activated in different tumours where they have causative roles in initiation, progression and metastasis. They can control a huge gene expression program by binding mainly to distal enhancers that can reach their target promoters through chromatin looping. In this research project we established a new functional link between YAP/TAZ and a BET family member, BRD4. YAP/TAZ physically engage the general coactivator BRD4, dictating the genome-wide association of BRD4 to chromatin. By genome-wide analysis we proved that YAP/TAZ-bound enhancers mediate recruitment of BRD4 and RNA-Pol II at YAP/TAZ-regulated promoters. In so doing, the YAP/TAZ-BRD4 axis confers transcriptional advantage to a broad number of genes that are primarily involved in cell proliferation. Elevated BRD4 overload at YAP/TAZ cis-regulatory regions makes YAP/TAZ target genes extremely vulnerable to BET inhibition.
We showed that by exploiting the requirement of BRD4 for YAP/TAZ-dependent gene expression, we can blunt through BET inhibitors YAP/TAZ pro-tumorigenic activity in several cell and tissue contexts, causing regression of pre-established YAP/TAZ-addicted neoplastic lesions, and even revert drug resistance to molecular target therapy. These results present a new window of opportunity for a rational use of BET inhibitors for the treatment of YAP/TAZ addicted tumors.

Abstract (a different language)

Le cellule tumorali per sostenere l’elevato ritmo di crescita richiamano un maggior numero di fattori trascrizionali e modificatori della cromatina, diventando dipendenti dagli stessi, portando così ad un globale aumento della trascrizione. La “transcriptional addiction” è un tema sempre più emergente nella biologia del cancro, ma ad oggi sia il meccanismo che i fattori coinvolti rimangono sconosciuti.
Si è ipotizzato che YAP e TAZ, due cofattori trascrizionali, potessero essere ottimi candidati per mediare queste dipendenze in differenti contesti cellulari. YAP/TAZ ricoprono un ruolo fondamentale nel cancro, prendendo parte nell’iniziazione, progressione ed induzione di metastasi. In questo progetto di ricerca abbiamo identificato un legame fisico e funzionale tra YAP/TAZ e un membro della famiglia delle proteine BET, BRD4. Tramite ChIP-seq abbiamo dimostrato che il già noto legame di YAP/TAZ a siti enhancers media il reclutamento di BRD4 sugli stessi siti e sui promotori dei geni regolati da YAP/TAZ, richiamando l’RNA polimerasi II e permettendo la successiva trascrizione dei geni a valle.
La relazione YAP/TAZ-BRD4 conferisce un vantaggio trascrizionale a geni principalmente coinvolti nella proliferazione e nel ciclo cellulare; allo stesso tempo però l’accumulo di BRD4 su queste regioni di cromatina conferisce una certa sensibilità ai target di YAP/TAZ all’azione di inibitori farmacologici delle proteine BET. L’azione inibitoria di queste molecole si è rivelata efficace anche in vivo su modelli di tumore dipendenti da YAP/TAZ e inoltre sulla capacità di sovvertire la resistenza al Vemurafenib in linee cellulari di melanoma. Questi risultati aprono una nuova finestra di opportunità terapeutiche dove i BET-inhibitors usati da soli o in combinazione con farmaci preesistenti possono contrastare l’attività pro-tumorigenica di YAP/TAZ in diversi tessuti.

EPrint type:Ph.D. thesis
Tutor:Piccolo, Stefano
Supervisor:Zanaconato, Francesca
Ph.D. course:Ciclo 31 > Corsi 31 > MEDICINA MOLECOLARE
Data di deposito della tesi:27 November 2018
Anno di Pubblicazione:26 November 2018
Key Words:YAP, TAZ, epigenetic, BRD4, cancer, transcriptional addiction
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Centri > Centro Interdipartimentale di servizi A. Vallisneri
Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:11403
Depositato il:06 Nov 2019 09:44
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