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

17 Citations (Scopus)

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 - Jan 1 2015

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Triple Negative Breast Neoplasms
Gene Regulatory Networks
Endoplasmic Reticulum Stress
YW3-56
p53 Genes
Autophagy
Regulator Genes
Growth
Heterografts
Nude Mice
Neoplasms
Mitochondria
Cell Death
Binding Sites
Breast Neoplasms
Gene Expression

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / ATF4 gene network mediates cellular response to the anticancer PAD inhibitor YW3-56 in triple-negative breast cancer cells. In: Molecular cancer therapeutics. 2015 ; Vol. 14, No. 4. pp. 877-888.
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ATF4 gene network mediates cellular response to the anticancer PAD inhibitor YW3-56 in triple-negative breast cancer cells. / 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.

In: Molecular cancer therapeutics, Vol. 14, No. 4, 01.01.2015, p. 877-888.

Research output: Contribution to journalArticle

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AU - Chan-Salis, Ka Yim

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AU - Chen, Gong

AU - Thomas, Craig

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AU - Wang, Yanming

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