Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes.
Epigenetic chromatin modification is a major regulator of eukaryotic gene expression, and aberrant epigenetic silencing of gene expression contributes to tumorigenesis. Histone modifications include acetylation, phosphorylation, and methylation, resulting in a combination of histone marks known collectively as the histone code. The chromatin marks at a given promoter determine, in part, whether specific promoters are in an open/active conformation or closed/repressed conformation. Dimethyl-lysine 4 histone H3 (H3K4me2) is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by the lysine-specific demethylase 1 (LSD1), a homologue of polyamine oxidases, may broadly repress gene expression. We now report that novel biguanide and bisguanidine polyamine analogues are potent inhibitors of LSD1. These analogues inhibit LSD1 in human colon carcinoma cells and affect a reexpression of multiple, aberrantly silenced genes important in the development of colon cancer, including members of the secreted frizzle-related proteins (SFRPs) and the GATA family of transcription factors. Furthermore, we demonstrate by chromatin immunoprecipitation analysis that the reexpression is concurrent with increased H3K4me2 and acetyl-H3K9 marks, decreased H3K9me1 and H3K9me2 repressive marks. We thus define important new agents for reversing aberrant repression of gene transcription.
Huang
Yi
Y
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, USA.
Greene
Eriko
E
Murray Stewart
Tracy
T
Goodwin
Andrew C
AC
Baylin
Stephen B
SB
Woster
Patrick M
PM
Casero
Robert A
RA
D001645:Biguanides / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050991:GATA4 Transcription Factor / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects*; D016147:Genes, Tumor Suppressor; D056466:Histone Demethylases; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D011073:Polyamines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D000094742:Secreted Frizzled-Related Proteins
D001645:Biguanides; D004791:Enzyme Inhibitors; D050991:GATA4 Transcription Factor; D056466:Histone Demethylases; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010089:Oxidoreductases, N-Demethylating; D011073:Polyamines; C484170:GATA4 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C495195:KDM1A protein, human