title: Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties.
abstract: Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties.
authors: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
authors: Jing
authors: J
authors: Wang
authors: Fei
authors: F
authors: Lu
authors: Qi
authors: Q
authors: Ren
authors: Hong
authors: H
authors: Sun
authors: Zhengshuang
authors: Z
authors: Xu
authors: Rongfeng
authors: R
authors: Lan
authors: Yuqing
authors: Y
authors: Liu
authors: David
authors: D
authors: Ward
authors: Junmin
authors: J
authors: Quan
authors: Tao
authors: T
authors: Ye
authors: Hui
authors: H
authors: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000201:enzymology / Q000378:metabolism; D057890:Epigenomics / Q000379:methods; D057809:HEK293 Cells; D006367:HeLa Cells; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D012680:Sensitivity and Specificity
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human