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Volume 18, Issue 5 (September 2016) 18, 695–703; DOI:10.4103/1008-682X.181818

Prostate-associated gene 4 (PAGE4), an intrinsically disordered cancer/testis antigen, is a novel therapeutic target for prostate cancer

Prakash Kulkarni1, A Keith Dunker2, Keith Weninger3, John Orban4

1 Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA
2 Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Informatics, Indianapolis, IN 46202, USA
3 Department of Physics, North Carolina State University, Raleigh, NC 27695, USA
4 Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850; Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA

Correspondence: Dr. P Kulkarni (pkulkar4@ibbr.umd.edu) or Dr. J Orban (jorban@umd.edu)



Prostate-associated gene 4 (PAGE4) is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein (IDP) that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun. c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer (PCa). Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease.

Keywords: prostate-associated Gene 4; cancer/testis antigen; intrinsically disordered protein; prostate cancer; c-Jun; AP-1; protein interaction networks; homeodomain-interacting protein 1

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