title: Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells.
abstract: Epigenetic gene silencing, mediated by aberrant promoter DNA hypermethylation and repressive histone modifications, is a hallmark of cancer. Although heritable, the dynamic nature and potential reversibility through pharmacological interventions make such aberrations attractive targets. Since cancers contain multiple epigenetic abnormalities, combining therapies that target different defects could potentially enhance their individual efficacies. 5-Aza-2'-deoxycytidine (5-Aza-CdR), FDA-approved drug for the treatment of myelodysplastic syndrome, can inhibit DNA methyltransferases (DNMTs) upon incorporation into the DNA of dividing cells, resulting in global demethylation. More recently, the first histone demethylase, lysine specific demethylase 1 (LSD1), which demethylates both histone and non-histone substrates, has become a new target for epigenetic therapy. Using, clorgyline, an LSD1 inhibitor (LSD1i) to treat cancer cell lines, we show that clorgyline employs two mechanisms of action depending on the cell type: it can either induce global DNA demethylation or inhibit LSD1-driven H3K4me2 and H3K4me1 demethylation to establish an active chromatin configuration. We also investigate the therapeutic efficacy of combining 5-Aza-CdR with clorgyline and determine that this combinatorial treatment has synergistic effects on reactivating aberrantly silenced genes by enriching H3K4me2 and H3K4me1. Many of the reactivated genes are categorized as cancer testis antigens or belong to the interferon-signaling pathway, suggesting potential implications for immunotherapy. Together, our results demonstrate that combinatorial treatment consisting of a DNMT inhibitor (DNMTi) and an LSD1i have enhanced therapeutic values and could improve the efficacy of epigenetic therapy.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy,University of Southern California, Los Angeles, California, United States of America ; Departments of Urology and Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern, California, Los Angeles, California, United States of America.
authors.forename: Han
authors.initials: H
authors.lastname: Han
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
authors.forename: Kurinji
authors.initials: K
authors.lastname: Pandiyan
authors.forename: Gangning
authors.initials: G
authors.lastname: Liang
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003010:Clorgyline / Q000494:pharmacology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020868:Gene Silencing / Q000187:drug effects*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D000077209:Decitabine; D056466:Histone Demethylases; C495195:KDM1A protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D003010:Clorgyline; D001374:Azacitidine
references.citation: Epigenetics. 2009 Apr 1;4(3):129-32
references.pmid: 19395867
references.citation: Nat Rev Cancer. 2005 Aug;5(8):615-25
references.pmid: 16034368
references.citation: Cancer Res. 2009 Mar 1;69(5):2065-71
references.pmid: 19223552
references.citation: Nat Rev Immunol. 2006 Nov;6(11):836-48
references.pmid: 17063185
references.citation: Cancer Res. 2002 Feb 15;62(4):961-6
references.pmid: 11861364
references.citation: Clin Cancer Res. 2011 May 1;17(9):2619-27
references.pmid: 21372217
references.citation: J Clin Oncol. 2011 Jan 20;29(3):330-6
references.pmid: 21149657
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7420-5
references.pmid: 12032298
references.citation: EMBO J. 1988 May;7(5):1395-402
references.pmid: 3409869
references.citation: Leukemia. 2011 Feb;25(2):226-35
references.pmid: 21116282
references.citation: Proc Natl Acad Sci U S A. 2004 May 11;101(19):7357-62
references.pmid: 15123803
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: Nature. 2003 Apr 17;422(6933):735-8
references.pmid: 12700765
references.citation: Nature. 2007 Sep 6;449(7158):105-8
references.pmid: 17805299
references.citation: Cancer Cell. 2010 May 18;17(5):510-22
references.pmid: 20399149
references.citation: Cell. 2004 Dec 29;119(7):941-53
references.pmid: 15620353
references.citation: Cancer Cell. 2012 Apr 17;21(4):473-87
references.pmid: 22464800
references.citation: Mol Carcinog. 2011 Dec;50(12):931-44
references.pmid: 21400613
references.citation: Mol Cell Biol. 1999 Oct;19(10):6690-8
references.pmid: 10490608
references.citation: Mol Cell Proteomics. 2008 Oct;7(10):2019-27
references.pmid: 18669619
references.citation: Hum Pathol. 2012 Aug;43(8):1300-7
references.pmid: 22245111
references.citation: Amino Acids. 2012 Feb;42(2-3):887-98
references.pmid: 21805138
references.citation: Cell. 2004 Dec 29;119(7):903-6
references.pmid: 15620348
references.citation: Nature. 2005 Sep 15;437(7057):436-9
references.pmid: 16079795
references.citation: Hum Pathol. 2011 Nov;42(11):1667-75
references.pmid: 21531005
references.citation: Nat Med. 2012 Mar 11;18(4):605-11
references.pmid: 22406747
references.citation: Carcinogenesis. 2010 Jan;31(1):27-36
references.pmid: 19752007
references.citation: Cell. 2007 Feb 23;128(4):683-92
references.pmid: 17320506
references.citation: Nat Genet. 2009 Jan;41(1):125-9
references.pmid: 19098913
references.citation: Clin Cancer Res. 2009 Dec 1;15(23):7217-28
references.pmid: 19934284
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1454-8
references.pmid: 11171972
references.citation: Oncology (Williston Park). 2011 Mar;25(3):220-6, 228
references.pmid: 21548464
references.citation: Cancer Cell. 2012 Apr 17;21(4):451-3
references.pmid: 22516254
references.citation: Nat Struct Mol Biol. 2011 Jul 03;18(8):867-74
references.pmid: 21725293
references.citation: Nat Rev Mol Cell Biol. 2012 Apr 04;13(5):297-311
references.pmid: 22473470
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: Carcinogenesis. 2010 Mar;31(3):512-20
references.pmid: 20042638
references.citation: BMC Med Genomics. 2009 Aug 20;2:55
references.pmid: 19691856
references.citation: Oncogene. 2002 Aug 12;21(35):5358-60
references.pmid: 12154398
references.citation: Nat Biotechnol. 2010 Oct;28(10):1069-78
references.pmid: 20944599
references.citation: Cell. 1980 May;20(1):85-93
references.pmid: 6156004
references.citation: PLoS Genet. 2012;8(3):e1002604
references.pmid: 22479200
references.citation: Epigenetics. 2006 Jul-Sep;1(3):116-20
references.pmid: 17786175
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14080-5
references.pmid: 16963560
references.citation: Future Oncol. 2010 May;6(5):717-32
references.pmid: 20465387
references.citation: Int J Cancer. 2011 Feb 1;128(3):574-86
references.pmid: 20333681