The <i>MDM2</i> inducible promoter folds into four-tetrad antiparallel G-quadruplexes targetable to fight malignant liposarcoma
Sara Lago, Matteo Nadai, Emanuela Ruggiero, Martina Tassinari, Maja Marušič, Beatrice Tosoni, Ilaria Frasson, Filippo M. Cernilogar, Valentina Pirota, Filippo Doria, Janez Plavec, Gunnar Schotta, Sara N. Richter
Abstract
Well-differentiated liposarcoma (WDLPS) is a malignant neoplasia hard to diagnose and treat. Its main molecular signature is amplification of the MDM2-containing genomic region. The MDM2 oncogene is the master regulator of p53: its overexpression enhances p53 degradation and inhibits apoptosis, leading to the tumoral phenotype. Here, we show that the MDM2 inducible promoter G-rich region folds into stable G-quadruplexes both in vitro and in vivo and it is specifically recognized by cellular helicases. Cell treatment with G-quadruplex-ligands reduces MDM2 expression and p53 degradation, thus stimulating cancer cell cycle arrest and apoptosis. Structural characterization of the MDM2 G-quadruplex revealed an extraordinarily stable, unique four-tetrad antiparallel dynamic conformation, amenable to selective targeting. These data indicate the feasibility of an out-of-the-box G-quadruplex-targeting approach to defeat WDLPS and all tumours where restoration of wild-type p53 is sought. They also point to G-quadruplex-dependent genomic instability as possible cause of MDM2 expansion and WDLPS tumorigenesis.