title: HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates.
abstract: Histone deacetylases (HDACs) and acetyltransferases have important roles in the regulation of protein acetylation, chromatin dynamics and the DNA damage response. Here, we show in human colon cancer cells that dietary isothiocyanates (ITCs) inhibit HDAC activity and increase HDAC protein turnover with the potency proportional to alkyl chain length, i.e., AITC < sulforaphane (SFN) < 6-SFN < 9-SFN. Molecular docking studies provided insights into the interactions of ITC metabolites with HDAC3, implicating the allosteric site between HDAC3 and its co-repressor. ITCs induced DNA double-strand breaks and enhanced the phosphorylation of histone H2AX, ataxia telangiectasia and Rad3-related protein (ATR) and checkpoint kinase-2 (CHK2). Depending on the ITC and treatment conditions, phenotypic outcomes included cell growth arrest, autophagy and apoptosis. Coincident with the loss of HDAC3 and HDAC6, as well as SIRT6, ITCs enhanced the acetylation and subsequent degradation of critical repair proteins, such as CtIP, and this was recapitulated in HDAC knockdown experiments. Importantly, colon cancer cells were far more susceptible than non-cancer cells to ITC-induced DNA damage, which persisted in the former case but was scarcely detectable in non-cancer colonic epithelial cells under the same conditions. Future studies will address the mechanistic basis for dietary ITCs preferentially exploiting HDAC turnover mechanisms and faulty DNA repair pathways in colon cancer cells vs. normal cells.
authors.affiliation: Linus Pauling Institute; Oregon State University; Corvallis, OR USA.
authors.forename: Praveen
authors.initials: P
authors.lastname: Rajendran
authors.forename: Ariam I
authors.initials: AI
authors.lastname: Kidane
authors.forename: Tian-Wei
authors.initials: TW
authors.lastname: Yu
authors.forename: Wan-Mohaiza
authors.initials: WM
authors.lastname: Dashwood
authors.forename: William H
authors.initials: WH
authors.lastname: Bisson
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.forename: Emily
authors.initials: E
authors.lastname: Ho
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Roderick H
authors.initials: RH
authors.lastname: Dashwood
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D045744:Cell Line, Tumor; D003106:Colon / Q000166:cytology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004706:Endodeoxyribonucleases; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism*; D013454:Sulfoxides
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D056572:Histone Deacetylase Inhibitors; D017879:Isothiocyanates; D009687:Nuclear Proteins; D013454:Sulfoxides; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; D006655:Histone Deacetylases; C016766:sulforaphane
keywords: CtIP acetylation; DNA damage; HDAC inhibition; HDAC3; SIRT6; colon cancer; epigenetics; repair