Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 2, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkaa1273
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Funding
- Italian Foundation for Cancer Research (AIRC) [21850]
- European Research Council (ERC-2013-CoG) [615879]
- Deutsche Forschungsgemeinschaft [SFB1064 -A11, SFB1243 -A03]
- Italian Foundation forCancerResearch (AIRC)
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Well-differentiated liposarcoma is a malignant neoplasm characterized by amplification of the MDM2 gene region, and targeting the MDM2 G-quadruplex can promote apoptosis in cancer cells. The research suggests that this approach may be beneficial for treating WDLPS and other tumors seeking to restore wild-type p53.
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.
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