title: Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors.
abstract: Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM.
authors.affiliation: Department of Pediatrics Research, The Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Singh
authors.forename: Christa A
authors.initials: CA
authors.lastname: Manton
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Bhat
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Tsai
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Barton
authors.forename: Joya
authors.initials: J
authors.lastname: Chandra
mesh_terms: D000107:Acetylation; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D014191:Tranylcypromine / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D008996:Monoamine Oxidase Inhibitors; D034741:RNA, Small Interfering; D014191:Tranylcypromine; D000077337:Vorinostat; D056466:Histone Demethylases; C495195:KDM1A protein, human; D020169:Caspases