Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2011-12, Vol.71 (23), p.7238-7249
Main Authors: JINGWANG, FEILU, HUI ZHANG, QI REN, HONG SUN, ZHENGSHUANG XU, RONGFENG LAN, YUQING LIU, WARD, David, JUNMIN OUAN, TAO YE
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation - drug effects
Embryonic Stem Cells - enzymology
Embryonic Stem Cells - metabolism
Epigenomics - methods
HEK293 Cells
HeLa Cells
Histone Demethylases - antagonists & inhibitors
Histone Demethylases - biosynthesis
Histone Demethylases - genetics
Histones - metabolism
Humans
Medical sciences
Metazoa
Methylation - drug effects
Mice
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - metabolism
Neoplasms - pathology
NIH 3T3 Cells
Octamer Transcription Factor-3 - biosynthesis
Octamer Transcription Factor-3 - genetics
Pharmacology. Drug treatments
Pluripotent Stem Cells - drug effects
Pluripotent Stem Cells - enzymology
Pluripotent Stem Cells - metabolism
Pluripotent Stem Cells - pathology
RNA Interference
Sensitivity and Specificity
SOXB1 Transcription Factors - biosynthesis
SOXB1 Transcription Factors - genetics
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-11-0896