NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss

Cancer Cell. 2006 May;9(5):367-78. doi: 10.1016/j.ccr.2006.03.031.

Abstract

We demonstrate that PTEN loss causes reduced NKX3.1 expression in both murine and human prostate cancers. Restoration of Nkx3.1 expression in vivo in Pten null epithelium leads to decreased cell proliferation, increased cell death, and prevention of tumor initiation. Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. Consistent with its tumor suppressor functions, NKX3.1 engages cell cycle and cell death machinery via association with HDAC1, leading to increased p53 acetylation and half-life through MDM2-dependent mechanisms. Importantly, overexpression of Nkx3.1 has little effect on Pten wild-type epithelium, suggesting that PTEN plays a predominant role in PTEN-NKX3.1 interplay. Manipulating NKX3.1 expression may serve as a therapeutic strategy for treating PTEN-deficient prostate cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Animals
  • Cell Proliferation
  • Down-Regulation / genetics
  • Enzyme Activation
  • Epithelium / metabolism
  • Epithelium / pathology
  • Gene Expression
  • Histone Deacetylase 1
  • Histone Deacetylases / metabolism
  • Homeodomain Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • Promoter Regions, Genetic / genetics
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Transcription Factors / metabolism*
  • Transplants
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • AR protein, human
  • Homeodomain Proteins
  • NKX3-1 protein, human
  • Nkx3-1 protein, mouse
  • Receptors, Androgen
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases