Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D.
The androgen receptor (AR) is a transcription factor that is pivotal for the development of prostate cancer. Here, we have identified two related histone demethylases, JMJD2A and JMJD2D, which form complexes with ligand-bound AR. We found that AR interacts through its ligand binding domain with JMJD2A and JMJD2D. On the other hand, JMJD2A utilizes its catalytic domain or C-terminus to bind to AR, and JMJD2D does so via its C-terminus. Further, overexpression of JMJD2A or D stimulates AR function and this is dependent on JMJD2 catalytic activity. Conversely, downregulation of JMJD2A, which is often overexpressed in prostate tumors, reduces basal transcription of the AR target gene, prostate-specific antigen, in LNCaP prostate cancer cells. Altogether, our data have identified a novel class of AR coactivators, whose (over)expression in prostate tumors could contribute to the constitutive activation of AR and thus to androgen-depletion independency of advanced prostate cancer cells.
Shin
Sook
S
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Guggenheim Building 1501A, 200 First Street SW, Rochester, MN 55905, USA.
Janknecht
Ralf
R
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D010088:Oxidoreductases / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; D006657:Histones; D011944:Receptors, Androgen; D014157:Transcription Factors; D010088:Oxidoreductases; D056484:Jumonji Domain-Containing Histone Demethylases; C521694:KDM4D protein, human; C494424:KDM4A protein, human; D010089:Oxidoreductases, N-Demethylating