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The pluripotency factor Nanog is directly upregulated by the Androgen Receptor in prostate cancer cells
Author(s) -
Kregel Steven,
Szmulewitz Russell Z.,
Griend Donald J. Vander
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.22870
Subject(s) - homeobox protein nanog , enzalutamide , androgen receptor , prostate cancer , cancer research , lncap , biology , cancer stem cell , sox2 , oncogene , cancer cell , cancer , stem cell , transcription factor , embryonic stem cell , microbiology and biotechnology , cell cycle , induced pluripotent stem cell , genetics , gene
BACKGROUND The Androgen Receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in all stages of prostate cancer progression, including progression to castration‐resistance following androgen‐deprivation therapy. Thus, identifying and targeting critical AR‐regulated genes is one potential method to block castration‐resistant cancer proliferation. Of particular importance are transcription factors that regulate stem cell pluripotency; many of these genes are emerging as critical oncogenes in numerous tumor cell types. Of these, Nanog has been previously shown to increase the self‐renewal and stem‐like properties of prostate cancer cells. Thus, we hypothesized that Nanog is a candidate AR target gene that may impart castration‐resistance. METHODS We modulated AR signaling in LNCaP prostate cancer cells and assayed for Nanog expression. Direct AR binding to the NANOG promoter was tested using AR Chromatin Immunoprecipation (ChIP) and analyses of publically available AR ChIP‐sequencing data‐sets. Nanog over‐expressing cells were analyzed for cell growth and cytotoxicity in response to the AR antagonist enzalutamide and the microtubule stabilizing agent docetaxel. RESULTS AR signaling upregulates Nanog mRNA and protein. AR binds directly to the NANOG promoter, and was not identified within 75 kb of the NANOGP8 pseudogene, suggesting the NANOG gene locus was preferentially activated. Nanog overexpression in LNCaP cells increases overall growth, but does not increase resistance to enzalutamide or docetaxel. CONCLUSIONS Nanog is a novel oncogenic AR target gene in prostate cancer cells, and stable expression of Nanog increases proliferation and growth of prostate cancer cells, but not resistance to enzalutamide or docetaxel. Prostate 74:1530–1543, 2014 . © 2014 Wiley Periodicals, Inc.