title: ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.
abstract: We previously reported that a pan-PAD inhibitor, YW3-56, activates p53 target genes to inhibit cancer growth. However, the p53-independent anticancer activity and molecular mechanisms of YW3-56 remain largely elusive. Here, gene expression analyses found that ATF4 target genes involved in endoplasmic reticulum (ER) stress response were activated by YW3-56. Depletion of ATF4 greatly attenuated YW3-56-mediated activation of the mTORC1 regulatory genes SESN2 and DDIT4. Using the ChIP-exo method, high-resolution genomic binding sites of ATF4 and CEBPB responsive to YW3-56 treatment were generated. In human breast cancer cells, YW3-56-mediated cell death features mitochondria depletion and autophagy perturbation. Moreover, YW3-56 treatment effectively inhibits the growth of triple-negative breast cancer xenograft tumors in nude mice. Taken together, we unveiled the anticancer mechanisms and therapeutic potentials of the pan-PAD inhibitor YW3-56.
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
authors.forename: Xiangyun Amy
authors.initials: XA
authors.lastname: Chen
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jian-Kang
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
authors.forename: Ka Yim
authors.initials: KY
authors.lastname: Chan-Salis
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Chemistry, Pennsylvania State University, State College, Pennsylvania.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland.
authors.forename: Craig
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania.
authors.forename: B Franklin
authors.initials: BF
authors.lastname: Pugh
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania. yuw12@psu.edu.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks; D006657:Histones / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D059372:Nucleotide Motifs; D011485:Protein Binding; D000076342:Protein-Arginine Deiminases; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D004791:Enzyme Inhibitors; D006657:Histones; D016159:Tumor Suppressor Protein p53; D051701:Activating Transcription Factor 4; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases