title: Chemopreventive agent 3,3'-diindolylmethane selectively induces proteasomal degradation of class I histone deacetylases.
abstract: 3,3'-Diindolylmethane (DIM) is an anticancer agent that induces cell cycle arrest and apoptosis through unknown mechanisms. Here, we report that DIM can selectively induce proteasome-mediated degradation of class I histone deacetylases (HDAC1, HDAC2, HDAC3, and HDAC8) without affecting the class II HDAC proteins. DIM induced downregulation of class I HDACs in human colon cancer cells in vitro and in vivo in tumor xenografts. HDAC depletion relieved HDAC-mediated transcriptional inhibition of the cyclin-dependent kinase inhibitors p21WAF1 and p27KIP2, significantly increasing their expression and triggering cell cycle arrest in the G(2) phase of the cell cycle. Additionally, HDAC depletion was associated with an induction of DNA damage that triggered apoptosis. Our findings indicate that DIM acts to selectively target the degradation of class I HDACs.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota 58108, USA.
authors.forename: Yongming
authors.initials: Y
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D004249:DNA Damage; D015536:Down-Regulation; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D050760:Cyclin-Dependent Kinase Inhibitor p27; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases; C016392:3,3'-diindolylmethane