title: Histone deacetylases 1 and 2 cooperate in regulating BRCA1, CHK1, and RAD51 expression in acute myeloid leukemia cells.
abstract: Resistance to chemotherapy and a high relapse rate highlight the importance of finding new therapeutic options for the treatment of acute myeloid leukemia (AML). Histone deacetylase (HDAC) inhibitors (HDACIs) are a promising class of drugs for the treatment of AML. HDACIs have limited single-agent clinical activities, but when combined with conventional or investigational drugs they have demonstrated favorable outcomes. Previous studies have shown that decreasing expression of important DNA damage repair proteins enhances standard chemotherapy drugs. In our recent studies, the pan-HDACI panobinostat has been shown to enhance conventional chemotherapy drugs cytarabine and daunorubicin in AML cells by decreasing the expression of BRCA1, CHK1, and RAD51. In this study, we utilized class- and isoform-specific HDACIs and shRNA knockdown of individual HDACs to determine which HDACs are responsible for decreased expression of BRCA1, CHK1, and RAD51 following pan-HDACI treatment in AML cells. We found that inhibition of both HDAC1 and HDAC2 was necessary to decrease the expression of BRCA1, CHK1, and RAD51, enhance cytarabine- or daunorubicin-induced DNA damage and apoptosis, and abrogate cytarabine- or daunorubicin-induced cell cycle checkpoint activation in AML cells. These findings may aid in the development of rationally designed drug combinations for the treatment of AML.
authors.affiliation: National Engineering Laboratory for AIDS Vaccine and Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.|Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Chengzhi
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.affiliation: National Engineering Laboratory for AIDS Vaccine and Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.|Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.|Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.affiliation: National Engineering Laboratory for AIDS Vaccine and Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, P. R. China.|Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.|Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.|Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism*; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D003630:Daunorubicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077767:Panobinostat; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000074084:THP-1 Cells; D014162:Transfection
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D003561:Cytarabine; D000077767:Panobinostat; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D003630:Daunorubicin
keywords: BRCA1; CHK1; HDAC; RAD51; acute myeloid leukemia