HOTAIR is a lncRNA overexpressed in several epithelial cancers and strongly correlated with invasion. This lncRNA was proven a pivotal element of the epithelial-mesenchymal transition (EMT), a trans-differentiation process triggering metastasis. Snail, master inducer of EMT, requires HOTAIR to recruit EZH2 on specific epithelial target genes (i.e., HNF4α, E-cadherin and HNF1α) and cause their repression. Here we designed a HOTAIR deletion mutant form, named HOTAIR-sbid, including the putative Snail-binding domain but depleted of the EZH2 binding domain. HOTAIR-sbid acted as a dominant negative of the endogenous HOTAIR. In both murine and human tumor cells, HOTAIR-sbid impaired the ability of HOTAIR to bind Snail and, in turn, trigger H3K27me3/EZH2-mediated repression of Snail epithelial target genes. Notably, HOTAIR-sbid expression was proven to reduce cellular motility, invasiveness, anchorage-independent growth, and responsiveness to TGFß-induced EMT. These data provide evidence on a lncRNA-based strategy to effectively impair the function of a master EMT-transcriptional factor.

Design and functional validation of a mutant variant of the lncRNA HOTAIR to counteract Snail function in Epithelial-to-Mesenchymal Transition / Battistelli, Cecilia; Garbo, Sabrina; Riccioni, Veronica; Montaldo, Claudia; Santangelo, Laura; Vandelli, Andrea; Strippoli, Raffaele; Tartaglia, GIAN GAETANO; Tripodi, Marco; Cicchini, Carla. - In: CANCER RESEARCH. - ISSN 0008-5472. - 81:1(2021), pp. 103-113. [10.1158/0008-5472.CAN-20-1764]

Design and functional validation of a mutant variant of the lncRNA HOTAIR to counteract Snail function in Epithelial-to-Mesenchymal Transition

Cecilia Battistelli
;
Sabrina Garbo;Veronica Riccioni;Laura Santangelo;Raffaele Strippoli;Gian Gaetano Tartaglia;Marco Tripodi
;
Carla Cicchini
2021

Abstract

HOTAIR is a lncRNA overexpressed in several epithelial cancers and strongly correlated with invasion. This lncRNA was proven a pivotal element of the epithelial-mesenchymal transition (EMT), a trans-differentiation process triggering metastasis. Snail, master inducer of EMT, requires HOTAIR to recruit EZH2 on specific epithelial target genes (i.e., HNF4α, E-cadherin and HNF1α) and cause their repression. Here we designed a HOTAIR deletion mutant form, named HOTAIR-sbid, including the putative Snail-binding domain but depleted of the EZH2 binding domain. HOTAIR-sbid acted as a dominant negative of the endogenous HOTAIR. In both murine and human tumor cells, HOTAIR-sbid impaired the ability of HOTAIR to bind Snail and, in turn, trigger H3K27me3/EZH2-mediated repression of Snail epithelial target genes. Notably, HOTAIR-sbid expression was proven to reduce cellular motility, invasiveness, anchorage-independent growth, and responsiveness to TGFß-induced EMT. These data provide evidence on a lncRNA-based strategy to effectively impair the function of a master EMT-transcriptional factor.
2021
Cancer; lncRNA; EMT
01 Pubblicazione su rivista::01a Articolo in rivista
Design and functional validation of a mutant variant of the lncRNA HOTAIR to counteract Snail function in Epithelial-to-Mesenchymal Transition / Battistelli, Cecilia; Garbo, Sabrina; Riccioni, Veronica; Montaldo, Claudia; Santangelo, Laura; Vandelli, Andrea; Strippoli, Raffaele; Tartaglia, GIAN GAETANO; Tripodi, Marco; Cicchini, Carla. - In: CANCER RESEARCH. - ISSN 0008-5472. - 81:1(2021), pp. 103-113. [10.1158/0008-5472.CAN-20-1764]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1471921
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