P300 acetyltransferase regulates androgen receptor degradation and pten-deficient prostate tumorigenesis

Jian Zhong, Liya Ding, Laura R. Bohrer, Yunqian Pan, Ping Liu, Jun Zhang, Thomas J. Sebo, Robert Jeffrey Karnes, Donald J. Tindall, Jan Van Deursen, Haojie Huang

Research output: Contribution to journalArticle

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Abstract

Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss.

Original languageEnglish (US)
Pages (from-to)1870-1880
Number of pages11
JournalCancer Research
Volume74
Issue number6
DOIs
StatePublished - Mar 15 2014

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Androgen Receptors
Prostate
Prostatic Neoplasms
Carcinogenesis
Histone Acetyltransferases
Acetylation
RNA Interference
Serine
p300-CBP-associated factor
Phosphorylation
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

P300 acetyltransferase regulates androgen receptor degradation and pten-deficient prostate tumorigenesis. / Zhong, Jian; Ding, Liya; Bohrer, Laura R.; Pan, Yunqian; Liu, Ping; Zhang, Jun; Sebo, Thomas J.; Karnes, Robert Jeffrey; Tindall, Donald J.; Van Deursen, Jan; Huang, Haojie.

In: Cancer Research, Vol. 74, No. 6, 15.03.2014, p. 1870-1880.

Research output: Contribution to journalArticle

Zhong, Jian ; Ding, Liya ; Bohrer, Laura R. ; Pan, Yunqian ; Liu, Ping ; Zhang, Jun ; Sebo, Thomas J. ; Karnes, Robert Jeffrey ; Tindall, Donald J. ; Van Deursen, Jan ; Huang, Haojie. / P300 acetyltransferase regulates androgen receptor degradation and pten-deficient prostate tumorigenesis. In: Cancer Research. 2014 ; Vol. 74, No. 6. pp. 1870-1880.
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