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

Mol Cancer Ther. 2015 Apr;14(4):877-88. doi: 10.1158/1535-7163.MCT-14-1093-T. Epub 2015 Jan 22.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Protein-Arginine Deiminases
  • 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

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • Enzyme Inhibitors
  • Histones
  • Tumor Suppressor Protein p53
  • Activating Transcription Factor 4
  • EIF2AK3 protein, human
  • eIF-2 Kinase
  • Hydrolases
  • Protein-Arginine Deiminases