TY - JOUR
T1 - Design and functional validation of a mutant variant of the lncRNA HOTAIR to counteract Snail function in Epithelial-to-Mesenchymal Transition
AU - Battistelli, Cecilia
AU - Garbo, Sabrina
AU - Riccioni, Veronica
AU - Montaldo, Claudia
AU - Santangelo, Laura
AU - Vandelli, Andrea
AU - Strippoli, Raffaele
AU - Tartaglia, Gian Gaetano
AU - Tripodi, Marco
AU - Cicchini, Carla
N1 - Copyright ©2020, American Association for Cancer Research.
PY - 2020/11/6
Y1 - 2020/11/6
N2 - 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.
AB - 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.
U2 - 10.1158/0008-5472.CAN-20-1764
DO - 10.1158/0008-5472.CAN-20-1764
M3 - Article
C2 - 33158813
SP - 1
EP - 11
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
ER -