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  • Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B.

Small Molecule Inhibitors of KDM5 Histone Demethylases Increase the Radiosensitivity of Breast Cancer Cells Overexpressing JARID1B.

Molecules (Basel, Switzerland) (2019-05-08)
Simone Pippa, Cecilia Mannironi, Valerio Licursi, Luca Bombardi, Gianni Colotti, Enrico Cundari, Adriano Mollica, Antonio Coluccia, Valentina Naccarato, Giuseppe La Regina, Romano Silvestri, Rodolfo Negri

Background: 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. Methods: 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). Results: 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. Conclusions: 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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RIPA Buffer
Cell Counting Kit - 8, for quantitation of viable cell number in proliferation and cytotoxicity assays
Propidium iodide, ≥94.0% (HPLC)
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
Phosphatase Inhibitor Cocktail 3, DMSO solution
Trypsin-EDTA solution, 1 ×, sterile-filtered, BioReagent, suitable for cell culture, 500 BAEE units porcine trypsin and 180 μg EDTA • 4Na per ml in Dulbecco′s PBS without calcium and magnesium
KDOAM25 hydrochloride hydrate, ≥98% (HPLC)
Anti-RLN3 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Anti-phospho-H2AFX (pSer139) antibody produced in rabbit, affinity isolated antibody

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