Upregulation and nuclear retention of the human histone demethylase LSD1 are correlated with aggressiveness and poor outcome of several cancer types, but the molecular mechanism of LSD1 nuclear import remains unclear. Here, we found that the N-terminal flexible region of LSD1 contains a nuclear localization signal (NLS), (112)RRKRAK(117). Mutation or deletion of the NLS completely abolished the nuclear import of LSD1, suggesting the motif is a bona fide NLS. More importantly, our GST pull-down assay showed that LSD1 physically interacts with three proteins of importin α family. In addition, our data suggest that the nuclear localization of LSD1 via the NLS is not a cell-type specific event. Thus, these findings demonstrate for the first time that the NLS motif within the N-terminal flexible domain of LSD1 is critical for its nuclear localization via interaction with importin α proteins.
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