CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy

Cancer Res. 2014 Apr 1;74(7):2050-61. doi: 10.1158/0008-5472.CAN-13-1659. Epub 2014 Feb 3.


Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbp(pc-/-);Pten(pc+/-) mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp(-/-); Pten(+/-) and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27(KIP1), and p21(CIP1). Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbp(pc-/-);Pten(pc+/-) mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer.

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

  • Animals
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenesis, Genetic*
  • Haploinsufficiency*
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Indoles / pharmacology
  • Male
  • Membrane Proteins / physiology
  • Mice
  • PTEN Phosphohydrolase / genetics*
  • PTEN Phosphohydrolase / physiology
  • Panobinostat
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology*
  • Phosphoproteins / physiology
  • Polycomb Repressive Complex 2 / physiology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / therapy
  • Proto-Oncogene Proteins c-akt / physiology
  • Sialoglycoproteins / genetics
  • Sialoglycoproteins / physiology*
  • ras GTPase-Activating Proteins / genetics


  • CDKN1B protein, human
  • DAB2IP protein, human
  • Histones
  • Hydroxamic Acids
  • Indoles
  • Membrane Proteins
  • Pag1 protein, mouse
  • Peptide Fragments
  • Phosphoproteins
  • Sialoglycoproteins
  • bone sialoprotein (35-62), human
  • ras GTPase-Activating Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Panobinostat
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase