Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model

Z. Wang, D. Xu, Hanfei Ding, Jaejik Kim, J. Zhang, T. Hai, Chunhong Yan

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten.

Original languageEnglish (US)
Pages (from-to)4975-4984
Number of pages10
JournalOncogene
Volume34
Issue number38
DOIs
StatePublished - Sep 17 2015

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Activating Transcription Factor 3
Knockout Mice
Prostatic Neoplasms
Prostate
Prostatic Intraepithelial Neoplasia
S 6
Neoplasms
Proteins
Matrix Metalloproteinase 9

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. / Wang, Z.; Xu, D.; Ding, Hanfei; Kim, Jaejik; Zhang, J.; Hai, T.; Yan, Chunhong.

In: Oncogene, Vol. 34, No. 38, 17.09.2015, p. 4975-4984.

Research output: Contribution to journalArticle

Wang, Z. ; Xu, D. ; Ding, Hanfei ; Kim, Jaejik ; Zhang, J. ; Hai, T. ; Yan, Chunhong. / Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. In: Oncogene. 2015 ; Vol. 34, No. 38. pp. 4975-4984.
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