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Pippa, Simone; Mannironi, Cecilia; Licursi, Valerio; Bombardi, Luca; Colotti, Gianni; Cundari, Enrico; Mollica, Adriano; Coluccia, Antonio; Naccarato, Valentina; La Regina, Giuseppe; Silvestri, Romano; Negri, Rodolfo
Molecules (Basel, Switzerland), 05/2019, Letnik: 24, Številka: 9Journal Article
: KDM5 enzymes are H3K4 specific histone demethylases involved in transcriptional regulation and DNA repair. These proteins are overexpressed in different kinds of cancer, including breast, prostate and bladder carcinomas, with positive effects on cancer proliferation and chemoresistance. For these reasons, these enzymes are potential therapeutic targets. : In the present study, we analyzed the effects of three different inhibitors of KDM5 enzymes in MCF-7 breast cancer cells over-expressing one of them, namely KDM5B/JARID1B. In particular we tested H3K4 demethylation (western blot); radio-sensitivity (cytoxicity and clonogenic assays) and damage accumulation (COMET assay and kinetics of H2AX phosphorylation). : we show that all three compounds with completely different chemical structures can selectively inhibit KDM5 enzymes and are capable of increasing sensitivity of breast cancer cells to ionizing radiation and radiation-induced damage. : These findings confirm the involvement of H3K4 specific demethylases in the response to DNA damage, show a requirement of the catalytic function and suggest new strategies for the therapeutic use of their inhibitors.
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in: SICRIS
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