title: Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma.
abstract: Given the fundamental roles of histone deacetylases (HDACs) in the regulation of DNA repair, replication, transcription and chromatin structure, it is fitting that therapies targeting HDAC activities are now being explored as anti-cancer agents. In fact, two histone deacetylase inhibitors (HDIs), SAHA and Depsipeptide, are FDA approved for single-agent treatment of refractory cutaneous T cell lymphoma (CTCL). An important target of these HDIs, histone deacetylase 3 (HDAC3), regulates processes such as DNA repair, metabolism, and tumorigenesis through the regulation of chromatin structure and gene expression. Here we show that HDAC3 inhibition using a first in class selective inhibitor, RGFP966, resulted in decreased cell growth in CTCL cell lines due to increased apoptosis that was associated with DNA damage and impaired S phase progression. Through isolation of proteins on nascent DNA (iPOND), we found that HDAC3 was associated with chromatin and is present at and around DNA replication forks. DNA fiber labeling analysis showed that inhibition of HDAC3 resulted in a significant reduction in DNA replication fork velocity within the first hour of drug treatment. These results suggest that selective inhibition of HDAC3 could be useful in treatment of CTCL by disrupting DNA replication of the rapidly cycling tumor cells, ultimately leading to cell death.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Wells
authors.forename: Srividya
authors.initials: S
authors.lastname: Bhaskara
authors.forename: Kristy R
authors.initials: KR
authors.lastname: Stengel
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Bianca
authors.initials: B
authors.lastname: Sirbu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chagot
authors.forename: David
authors.initials: D
authors.lastname: Cortez
authors.forename: Dineo
authors.initials: D
authors.lastname: Khabele
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Chazin
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooper
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacques
authors.forename: James
authors.initials: J
authors.lastname: Rusche
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eischen
authors.forename: Laura Y
authors.initials: LY
authors.lastname: McGirt
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000473:pathology*; D016196:S Phase / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D000099186:Histone Deacetylase 3
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3
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