SABRINA GARBO

Dottoressa di ricerca

ciclo: XXXIII


supervisore: Prof. Marco Tripodi
relatore: Prof. Marco Tripodi

Titolo della tesi: Design and functional validation of a lncRNA-based strategy to counteract EMT

EMT (Epithelial to Mesenchymal Transition) is a trans-differentiation program in which epithelial cells acquire a new mesenchymal phenotype. The host laboratory has highlighted a circuitry of reciprocal regulation of master transcriptional factors involved in the EMT/MET dynamics. Importantly, SNAIL, the master transcriptional factor of EMT, sufficient to promote the induction of this cellular process, modulates cell morphology, activates mesenchymal genes expression (i.e. MMP2 and MMP9), but above all represses HNF4α through the direct binding to its promoter (Cicchini et al., 2006). In contrast, HNF4α, master gene of MET and hepatic differentiation, is able to activate the expression of epithelial genes and to repress the mesenchymal ones like SNAIL itself (Santangelo et al., 2011). This circuitry has been enriched by the analysis of the role of microRNAs (Garibaldi et al., 2012) and epigenetic mechanisms of gene regulation (Cicchini et al., 2015). In the frame of different studies focusing on the involvement of the lncRNA HOTAIR in several epithelial cancer development and dissemination, the host laboratory has recently investigated its role in the EMT, a process allowing invasion of tumor cells in secondary sites, and required for metastasis. Mechanistically, the master transcriptional factor SNAIL, sufficient to induce and to maintain EMT, binds to HOTAIR to recruit EZH2 to specific epithelial genes (that will undergo EZH2-induced chromatin repressive modifications). In other words, HOTAIR is required for the SNAIL-mediated repression (Battistelli et al., 2017). Moreover, HOTAIR transcription was found directly repressed by HNF4α through a chromatin structure reorganization (Battistelli et al., 2019). Overall, these findings defined an additional level of gene regulation. On the basis of this body of evidence, my research pointed to the design of a HOTAIR deletion mutant able to interfere with the SNAIL/HOTAIR/EZH2 complex formation in EMT/MET dynamics. In particular, the bioinformatic prediction of HOTAIR structures and interactions allowed the identification of the HOTAIR putative SNAIL-binding domain (HOTAIR-sbid). The functional validation of this mutant in transitional cells demonstrated its role as a dominant negative regulator of wild type HOTAIR, antagonizing HOTAIR/SNAIL/EZH2-mediated epithelial gene repression in EMT. In both murine and human liver tumour cells, HOTAIR-sbid impairs HOTAIR ability to: (i) bind to SNAIL and, in turn, (ii) trigger H3K27me3/EZH2-mediated repression of Snail epithelial target genes (HNF4α, E-cadherin and HNF1α). Functionally, HOTAIR-sbid reduces cellular motility, invasion abilities and responsiveness to TGFß-induced EMT (Battistelli, Garbo et al., 2020). These data provide evidence on an lncRNA-based strategy effective to impair the function of the master EMT transcriptional factor SNAIL.

Produzione scientifica

  • 11573/1684985 - 2023 - Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells (01a Articolo in rivista)
    ZWERGEL, CLEMENS; AVENTAGGIATO, MICHELE; GARBO, SABRINA; DI BELLO, ELISABETTA; NOCE, BEATRICE; CASTIELLO, CAROLA; LAMBONA, CHIARA; BARRECA, FEDERICA; ROTILI, DANTE; FIORAVANTI, ROSSELLA; TRIPODI, MARCO; BATTISTELLI, CECILIA; TAFANI, MARCO; VALENTE, SERGIO; MAI, ANTONELLO
  • 11573/1680931 - 2022 - lncRNA HOTAIR functions and therapeutic perspectives (01h Abstract in rivista)
    GARBO, SABRINA; TRIPODI, MARCO; BATTISTELLI, CECILIA
  • 11573/1120944 - 2018 - The lncRNA H19 positively affects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter (01a Articolo in rivista)
    GARBO, SABRINA; BATTISTELLI, CECILIA; CICCHINI, CARLA
  • 11573/1605129 - 2022 - SYNCRIP Modulates the Epithelial-Mesenchymal Transition in Hepatocytes and HCC Cells (01a Articolo in rivista)
    RICCIONI, VERONICA; TRIONFETTI, FLAVIA; GARBO, SABRINA; MAROCCO, FRANCESCO; BATTISTELLI, CECILIA; MARCHETTI, ALESSANDRA; STRIPPOLI, RAFFAELE; AMICONE, LAURA; CICCHINI, CARLA; TRIPODI, MARCO
  • 11573/1659806 - 2022 - Restoration of WT1/miR-769-5p axis by HDAC1 inhibition promotes MMT reversal in mesenchymal-like mesothelial cells (01a Articolo in rivista)
    BONTEMPI, GIULIO; TERRI, MICHELA; GARBO, SABRINA; MONTALDO, CLAUDIA; VALENTE, SERGIO; ZWERGEL, CLEMENS; MAI, ANTONELLO; MARCHETTI, ALESSANDRA; MENE', PAOLO; BATTISTELLI, CECILIA; TRIPODI, MARCO; STRIPPOLI, RAFFAELE
  • 11573/1471921 - 2021 - Design and functional validation of a mutant variant of the lncRNA HOTAIR to counteract Snail function in Epithelial-to-Mesenchymal Transition (01a Articolo in rivista)
    BATTISTELLI, CECILIA; GARBO, SABRINA; RICCIONI, VERONICA; SANTANGELO, LAURA; STRIPPOLI, RAFFAELE; TARTAGLIA, GIAN GAETANO; TRIPODI, MARCO; CICCHINI, CARLA
  • 11573/1552435 - 2021 - m6A RNA methylation and beyond - the epigenetic machinery and potential treatment options (01g Articolo di rassegna (Review))
    GARBO, SABRINA; ZWERGEL, CLEMENS; BATTISTELLI, CECILIA
  • 11573/1613679 - 2021 - A novel RNA-based approach to counteract EMT (01m Editorial/Introduzione in rivista)
    GARBO, SABRINA; TRIPODI, MARCO; BATTISTELLI, CECILIA
  • 11573/1627263 - 2022 - SYNCRIP modulates the epithelial-mesenchymal transition in hepatocytes and HCC Cells (04f Poster)
    RICCIONI, VERONICA; TRIONFETTI, FLAVIA; GARBO, SABRINA; MAROCCO, FRANCESCO; BATTISTELLI, CECILIA; MARCHETTI, ALESSANDRA; STRIPPOLI, RAFFAELE; AMICONE, LAURA; CICCHINI, CARLA; TRIPODI, MARCO
  • 11573/1650846 - 2022 - Next RNA therapeutics: the mine of non-coding (01g Articolo di rassegna (Review))
    GARBO, SABRINA; MAIONE, ROSSELLA; TRIPODI, MARCO; BATTISTELLI, CECILIA
  • 11573/1655432 - 2022 - Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma (01a Articolo in rivista)
    GARBO, SABRINA; DI BELLO, ELISABETTA; FIORAVANTI, ROSSELLA; BATTISTELLI, CECILIA; ZWERGEL, CLEMENS
  • 11573/1660735 - 2022 - MyoD-Induced Trans-Differentiation: A Paradigm for Dissecting the Molecular Mechanisms of Cell Commitment, Differentiation and Reprogramming (01g Articolo di rassegna (Review))
    BATTISTELLI, CECILIA; GARBO, SABRINA; MAIONE, ROSSELLA
  • 11573/1663202 - 2023 - Selenium-Containing Agents Acting on Cancer—A New Hope? (01g Articolo di rassegna (Review))
    GARBO, SABRINA; DI GIACOMO, SILVIA; DI SOTTO, ANTONELLA; FIORAVANTI, ROSSELLA; ZWERGEL, CLEMENS; BATTISTELLI, CECILIA

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