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Androgen receptor (AR) suppresses normal human prostate epithelial cell proliferation via AR/β‐catenin/TCF‐4 complex inhibition of c‐MYC transcription
Author(s) -
Antony Lizamma,
van der Schoor Freek,
Dalrymple Susan L.,
Isaacs John T.
Publication year - 2014
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22828
Subject(s) - wnt signaling pathway , androgen receptor , paracrine signalling , cell growth , protein kinase b , cancer research , biology , transcription factor , signal transduction , microbiology and biotechnology , endocrinology , medicine , chemistry , receptor , prostate cancer , biochemistry , cancer , gene
INTRODUCTION Physiologic testosterone continuously stimulates prostate stromal cell secretion of paracrine growth factors (PGFs), which if unopposed would induce hyperplastic overgrowth of normal prostate epithelial cells (PrECs). METHODS Lentiviral shRNA stable knock down of c‐ MYC , β‐catenin, or TCF‐4 completely inhibits normal (i.e., non‐transformed) human PrECs growth. c‐ MYC enhancer driven reporter expression and growth is inhibited by two chemically distinct molecules, which prevent β‐catenin signaling either by blocking TCF‐4 binding (i.e., toxoflavin) or by stimulating degradation (i.e., AVX939). Recombinant DKK1 protein at a dose, which inhibits activation of canonical Wnt signaling does not inhibit PrEC growth. Nuclear β‐catenin translocation and PrEC growth is prevented by both lack of PGFs or Akt inhibitor‐I. Growth inhibition induced by lack of PGFs, toxoflavin, or Akt inhibitor‐I is overcome by constitutive c‐ MYC transcription. RESULTS In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen binding to AR suppressing c‐ MYC transcription, resulting in G 0 arrest/terminal differentiation independent of Rb, p21, p27, FoxP3, or down regulation of growth factors receptors and instead involves androgen‐induced formation of AR/β‐catenin/TCF‐4 complexes, which suppress c‐ MYC transcription. Such suppression does not occur when AR is mutated in its zinc‐finger binding domain. DISCUSSION Proliferation of non‐transformed human PrECs is dependent upon c‐ MYC transcription via formation/binding of β‐catenin/TCF‐4 complexes at both 5′ and 3′ c‐ MYC enhancers stimulated by Wnt‐independent, PGF induced Akt signaling. In the presence of continuous PGF signaling, PrEC hyperplasia is prevented by androgen‐induced formation of AR/β‐catenin/TCF‐4 complexes, which retains binding to 3′ c‐ MYC enhancer, but now suppresses c‐ MYC transcription. Prostate 74:1118–1131, 2014 . © 2014 Wiley Periodicals, Inc.