Central role for PELP1 in nonandrogenic activation of the androgen receptor in prostate cancer

Lin Yang, Preethi Ravindranathan, Meera Ramanan, Payal Kapur, Stephen R. Hammes, Jer Tsong Hsieh, Ganesh V. Raj

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

The ability of 17β-estradiol (E2) to regulate the proliferation of prostate cancer (PCa) cells in the absence of androgen is poorly understood. Here, we show the predominant estrogen receptor (ER) isoform expressed in PCa specimens and cell lines is ERβ. Our data indicate that E2 induces the formation of a complex between androgen receptor (AR), ERβ, and a proline-, glutamic acid-, and leucine-rich cofactor protein 1 (PELP1) in PCa cells. This protein complex is formed on AR's cognate DNA-responsive elements on the promoter in response to E2. Formation of this complex enables the transcription of AR-responsive genes in response to E2. Knockdown of PELP1, AR, or ERβ blocks the assembly of this complex, blocks E2-induced genomic activation of AR-regulated genes, and blocks E2-stimulated proliferation of PCa cells. Overall, this study shows that PELP1 may enable E2-induced AR signaling by forming a protein complex between AR, ERβ, and PELP1 on the DNA, leading to the proliferation of PCa cells in the absence of androgen. PELP1 may bridge the signal between E2 bound to ERβ and AR and thus allow for cross talk between these steroid receptors. These data suggest a novel mechanism of AR activation in the absence of androgens in PCa cells. Our data indicate that disruption of the complex between AR and PELP1 may be a viable therapeutic strategy in advanced PCa.

Original languageEnglish (US)
Pages (from-to)550-561
Number of pages12
JournalMolecular Endocrinology
Volume26
Issue number4
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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