A NR2E1-Interacting Peptide of LSD1 Inhibits the Proliferation of Brain Tumor Initiating Cells

Abstract The recurrence of malignant brain tumor, like glioblastoma, is often due to the existence of brain tumor initiating cells (BTICs) with stem cell properties. As the mortality ratio of brain tumor relapsed patients is very high and lack of efficient therapies, there is an urgent need to develop novel therapeutic methods targeting BTICs. NR2E1 (TLX), an orphan nuclear receptor, is critical for the self-renewal of BTICs. In this study, we found that NR2E1 recruits LSD1, a lysine demethylase, to demethylate mono- and di-methylated histone 3 Lys4 (H3K4me/me2) at the Pten promoters and repress its expression, thereby promoting BTIC proliferation. Using Amide Hydrogen/Deuterium Exchange and Mass Spectrometry (HDX-MS) method, we identified four LSD1 peptides that may interact with NR2E1. One of the peptides that locates at the LSD1 SWIRM domain strongly inhibited BTIC proliferation by promoting Pten expression through interfering NR2E1 and LSD1 function. Furthermore, overexpression of this peptide in human BTIC can inhibit its formation of brain tumor. Hence, this peptide exhibits an interesting potential for therapeutic intervention in malignant brain tumors in future.