Androgen receptor requires JunD as a coactivator to switch on an oxidative stress generation pathway in prostate cancer cells.
Relatively high oxidative stress levels in the prostate are postulated to be a major factor for prostate carcinogenesis and prostate cancer (CaP) progression. We focused on elucidating metabolic pathways of oxidative stress generation in CaP cells. Previously, we showed that the transcription factor JunD is essential for androgen-induced reactive oxygen species (ROS) production in androgen-dependent human CaP cells. We also recently showed that androgen induces the first and regulatory enzyme spermidine/spermine N1-acetyltransferase (SSAT) in a polyamine catabolic pathway that produces copious amounts of metabolic ROS. Here, we present coimmunoprecipitation and Gaussia luciferase reconstitution assay data that show that JunD forms a complex with androgen-activated androgen receptor (AR) in situ. Our chromatin immunoprecipitation assay data show that JunD binds directly to a specific SSAT promoter sequence only in androgen-treated LNCaP cells. Using a vector containing a luciferase reporter gene connected to the SSAT promoter and a JunD-silenced LNCaP cell line, we show that JunD is essential for androgen-induced SSAT gene expression. The elucidation of JunD-AR complex inducing SSAT expression leading to polyamine oxidation establishes the mechanistic basis of androgen-induced ROS production in CaP cells and opens up a new prostate-specific target for CaP chemopreventive/chemotherapeutic drug development.
Mehraein-Ghomi
Farideh
F
University of Wisconsin Carbone Cancer Center and Departments of Oncology and Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Basu
Hirak S
HS
Church
Dawn R
DR
Hoffmann
F Michael
FM
Wilding
George
G
D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000728:Androgens; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D000099228:Diamine N-Acetyltransferase
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