ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.

Therapeutic Approaches

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

Wang, Shu; Chen, Xiangyun Amy; Hu, Jing; Jiang, Jian-Kang; Li, Yunfei; Chan-Salis, Ka Yim; Gu, Ying; Chen, Gong; Thomas, Craig; Pugh, B Franklin; Wang, Yanming;

Keywords

  • Activating Transcription Factor 4/ metabolism
  • Animals
  • Autophagy/ drug effects
  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-beta/ metabolism
  • Cell Line, Tumor
  • Cell Proliferation/ drug effects
  • Chromatin Immunoprecipitation
  • Cluster Analysis
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress/ genetics
  • Enzyme Inhibitors/ pharmacology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic/ drug effects
  • Gene Regulatory Networks
  • Histones/ metabolism
  • Humans
  • Hydrolases/ antagonists & inhibitors
  • Mice
  • Mitochondria/ drug effects
  • Mitochondria/ metabolism
  • Mutation
  • Nucleotide Motifs
  • Protein Binding
  • Signal Transduction/ drug effects
  • Triple Negative Breast Neoplasms/ drug therapy
  • Triple Negative Breast Neoplasms/ genetics
  • Triple Negative Breast Neoplasms/ metabolism
  • Triple Negative Breast Neoplasms/ pathology
  • Tumor Burden/ drug effects
  • Tumor Suppressor Protein p53/ genetics
  • Xenograft Model Antitumor Assays
  • eIF-2 Kinase/ metabolism

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