ATF4 gene network mediates cellular response to the anticancer PAD inhibitor YW3-56 in triple-negative breast cancer cells

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

Research output: Contribution to journalArticle

24 Scopus citations

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 andmolecularmechanisms 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.

Original languageEnglish (US)
Pages (from-to)877-888
Number of pages12
JournalMolecular cancer therapeutics
Volume14
Issue number4
DOIs
StatePublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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