title: Role of ATF3 in synergistic cancer cell killing by a combination of HDAC inhibitors and agonistic anti-DR5 antibody through ER stress in human colon cancer cells.
abstract: Histone deacetylase inhibitors (HDACIs) are promising agents for cancer therapy. However, the mechanism(s) responsible for the efficacy of HDACIs have not yet to be fully elucidated. Death receptor 5 (DR5) is a transmembrane receptor containing death domain that triggers cell death upon binding to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or agonistic anti-DR5 monoclonal antibody, and the combination of TRAIL/agonistic anti-DR5 monoclonal antibody and agents that increase the expression of DR5 is expected as a novel anticancer therapeutic strategy. Here we report that six different HDACIs activated endoplasmic reticulum (ER) stress sensor PERK and eIF2α and induced the ATF4/ATF3/CHOP pathway in p53-deficient human colon cancer cells. This resulted in an increased expression of DR5 on the cell surface and sensitized cells to apoptosis by agonistic anti-DR5 monoclonal antibody. Stress response gene ATF3 was required for efficient DR5 induction by HDACIs, and DR5 reporter assay showed that ATF3 play crucial role for the HDACIs-induced activation of DR5 gene transcription. These provide important mechanistic insight into how HDACIs exhibit pro-apoptotic activity in clinical anti-cancer treatments when they are used in combination with other therapeutic strategies.
authors: Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China; Department of Thyroid Surgery, First Hospital of Jilin University, Changchun, Jilin 130021, China.
authors: Jia
authors: J
authors: Liu
authors: Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Makoto
authors: M
authors: Edagawa
authors: Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Hiroto
authors: H
authors: Goshima
authors: Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Makoto
authors: M
authors: Inoue
authors: Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors: Hideo
authors: H
authors: Yagita
authors: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin 130021, China. Electronic address: liuzh@jlu.edu.cn.
authors: Zhonghui
authors: Z
authors: Liu
authors: Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address: kita.bgen@mri.tmd.ac.jp.
authors: Shigetaka
authors: S
authors: Kitajima
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000911:Antibodies, Monoclonal; C497249:DDIT3 protein, human; D056572:Histone Deacetylase Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: ATF3; Agonistic anti-DR5 antibody; DR5; ER stress; HDACI