title: The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells.
abstract: Epigenetic modifying enzymes have a crucial role in the pathogenesis of acute myeloid leukemia (AML). Methylation of lysine 9 on histone H3 by the methyltransferase G9a and SUV39H1 is associated with inhibition of tumor suppressor genes. We studied the effect of G9a and SUV39H1 inhibitors on viability and differentiation of AML cells and tested the cytotoxicity induced by combination of G9a and SUV39H1 inhibitors and various epigenetic drugs. The SUV39H1 inhibitor (chaetocin) and the G9a inhibitor (UNC0638) caused cell death in AML cells at high concentrations. However, only chaetocin-induced CD11b expression and differentiation of AML cells at non-cytotoxic concentration. HL-60 and KG-1a cells were more sensitive to chaetocin than U937 cells. Long-term incubation of chaetocin led to downregulation of SUV39H1 and reduction of H3K9 tri-methylation in HL-60 and KG-1a cells. Combination of chaetocin with suberoylanilide hydroxamic acid (SAHA, a histone deacetylase inhibitor) or JQ (a BET (bromodomain extra terminal) bromodomain inhibitor) showed synergistic cytotoxicity. Conversely, no synergism was found by combining chaetocin and UNC0638. More importantly, chaetocin-induced differentiation and combined cytotoxicity were also found in the primary cells of AML patients. Collectively, the SUV39H1 inhibitor chaetocin alone or in combination with other epigenetic drugs may be effective for the treatment of AML.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Lai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chen
authors.affiliation: 1] National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan [2] Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Tsai
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Chen
authors.affiliation: 1] National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan [2] Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Hung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects*; D004357:Drug Synergism; D044127:Epigenesis, Genetic; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D012097:Repressor Proteins; C002511:chaetocin; C407843:SUV39H1 protein, human; D008780:Methyltransferases