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

Liya Ding, Shuai Chen, Ping Liu, Yunqian Pan, Jian Zhong, Kevin M. Regan, Liguo Wang, Chunrong Yu, Anthony Rizzardi, Liang Cheng, Jun Zhang, Stephen C. Schmechel, John C. Cheville, Jan Van Deursen, Donald J. Tindall, Haojie Huang

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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. Cbppc-/-;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 p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc-/-;Ptenpc+/- 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.

Original languageEnglish
Pages (from-to)2050-2061
Number of pages12
JournalCancer Research
Volume74
Issue number7
DOIs
StatePublished - Apr 1 2014

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Haploinsufficiency
Epigenomics
Prostatic Neoplasms
Histones
Prostate
Histone Code
Prostatic Intraepithelial Neoplasia
Therapeutics
Histone Deacetylase Inhibitors
Methyltransferases
Neoplasms
Phosphorylation
Cell Proliferation
Mortality
Incidence
Growth
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer : Implications for epigenetic therapy. / Ding, Liya; Chen, Shuai; Liu, Ping; Pan, Yunqian; Zhong, Jian; Regan, Kevin M.; Wang, Liguo; Yu, Chunrong; Rizzardi, Anthony; Cheng, Liang; Zhang, Jun; Schmechel, Stephen C.; Cheville, John C.; Van Deursen, Jan; Tindall, Donald J.; Huang, Haojie.

In: Cancer Research, Vol. 74, No. 7, 01.04.2014, p. 2050-2061.

Research output: Contribution to journalArticle

Ding, L, Chen, S, Liu, P, Pan, Y, Zhong, J, Regan, KM, Wang, L, Yu, C, Rizzardi, A, Cheng, L, Zhang, J, Schmechel, SC, Cheville, JC, Van Deursen, J, Tindall, DJ & Huang, H 2014, 'CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: Implications for epigenetic therapy', Cancer Research, vol. 74, no. 7, pp. 2050-2061. https://doi.org/10.1158/0008-5472.CAN-13-1659
Ding, Liya ; Chen, Shuai ; Liu, Ping ; Pan, Yunqian ; Zhong, Jian ; Regan, Kevin M. ; Wang, Liguo ; Yu, Chunrong ; Rizzardi, Anthony ; Cheng, Liang ; Zhang, Jun ; Schmechel, Stephen C. ; Cheville, John C. ; Van Deursen, Jan ; Tindall, Donald J. ; Huang, Haojie. / CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer : Implications for epigenetic therapy. In: Cancer Research. 2014 ; Vol. 74, No. 7. pp. 2050-2061.
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