Cytoplasmic translocation of nuclear lysine-specific demethylase-1 (LSD1/KDM1A) in human hepatoma cells is induced by its inhibitors

ABSTRACT Histone-modifiable lysine-specific demethylase-1 (LSD1/KDM1A) is often upregulated in many cancers, including hepatoma, and is regarded as oncoprotein. We previously reported that the hepatoma-preventive geranylgeranoic acid (GGA) inhibits KDM1A activity at the same IC 50 as that of the clinically used drug tranylcypromine, a verified inhibitor of KDM1A. Here, we report that these inhibitors induced cytoplasmic translocation of nuclear KDM1A in a human hepatoma-derived cell line. Immunofluorescence studies revealed cytoplasmic localization of KDM1A, 3 h after addition of GGA or tranylcypromine in HuH-7 cells. Geranylgeraniol and all- trans retinoic acid were both unable to induce translocation of nuclear KDM1A, whereas farnesoic acid showed the weak activity. Furthermore, GGA did not affect subcellular localization of another histone lysine-specific demethylase, KDM5A. This suggests that the inhibitor-induced translocation of nuclear KDM1A to the cytoplasm is specific for KDM1A. These data demonstrate for the first time that KDM1A inhibitors specifically induce the cytoplasmic translocation of nuclear KDM1A. Abbreviations ATRA all- trans retinoic acid CoREST corepressor for element 1-silencing transcription factor DIC differential interference contrast FA farnesoic acid GGOH geranylgeraniol GGA geranylgeranoic acid LSD1/KDM1A lysine-specific demethylase-1 pHH3 phospho-histone H3(Ser10) TCP trans -2-phenylcyclopropylamine